[ CAS No. 112022-83-0 ] {[proInfo.proName]}

Name: 112022-83-0|(R)-1-Methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole|97%
Brand: Ambeed
SKU: A855211
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Quality Control of [ 112022-83-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 112022-83-0 ]

SDS Specification

Alternatived Products of [ 112022-83-0 ]

Product Details of [ 112022-83-0 ]

CAS No. :	112022-83-0	MDL No. :	MFCD00078440
Formula :	C₁₈H₂₀BNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VMKAFJQFKBASMU-QGZVFWFLSA-N
M.W :	277.17	Pubchem ID :	9838490
Synonyms :

Calculated chemistry of [ 112022-83-0 ]

Physicochemical Properties

Num. heavy atoms :	21
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.33
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	90.29
TPSA :	12.47 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	4.13
Log Po/w (WLOGP) :	3.05
Log Po/w (MLOGP) :	3.01
Log Po/w (SILICOS-IT) :	2.22
Consensus Log Po/w :	2.48

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-4.45
Solubility :	0.00981 mg/ml ; 0.0000354 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.1
Solubility :	0.0221 mg/ml ; 0.0000797 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.56
Solubility :	0.00077 mg/ml ; 0.00000278 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.13

Safety of [ 112022-83-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P270-P280-P305+P351+P338-P310-P330-P403-P501	UN#:	N/A
Hazard Statements:	H302-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 112022-83-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 112022-83-0 ]
Downstream synthetic route of [ 112022-83-0 ]

[ 112022-83-0 ] Synthesis Path-Upstream 1~3

1
[ 77-78-1 ]
[ 112022-83-0 ]
[ 144119-12-0 ]

Reference： [1] Tetrahedron Letters, 2007, vol. 48, # 12, p. 2123 - 2125

2
[ 100331-89-3 ]
[ 112022-83-0 ]
[ 530084-79-8 ]

Reference： [1] Patent: WO2004/16578, 2004, A2, . Location in patent: Page 37

3
[ 100331-89-3 ]
[ 112022-83-0 ]
[ 530084-79-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	liquid HCl	Step 2: (R)-8-(Benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one 8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol) and (R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen. The suspension was cooled to -20° C. (external temperature) and borane dimethyl sulfide (BH₃-Me₂S) complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. After complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mL). The reaction was warmed to RT over 20 minutes. The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours. After this time the solid was collected by filtration and washed with water (3100 mL). The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent). ¹H NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H); 8.19 (d, J=9.9 Hz, 1H); 7.58 (d, J=7.5 Hz, 2H); 7.41-7.36 (m, 2H); 7.34-7.29 (m, 1H); 7.23-7.19 (m, 2H); 6.57 (d, J=9.8 Hz, 1H); 5.94 (d, J=4.7 Hz, 1H); 5.31 (s, 2H); 5.25-5.19 (m, 1H); 3.71-3.58 (m, 2H).

Reference： [1] Patent: US2014/161736, 2014, A1, . Location in patent: Page/Page column

[ 112022-83-0 ] Synthesis Path-Downstream 1~37

1
[ 823-96-1 ]
[ 22348-32-9 ]
[ 112022-83-0 ]

Yield	Reaction Conditions	Operation in experiment
	With borane; In toluene; at 20 - 150℃; for 4.5h;	(R)-(+)-alpha,alpha-Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 min. The mixture was placed in a 150 C. oil bath and liquid was distilled off. Toluene was added in 20 mL aliquots and distillation was continued for 4 h. A total of 300 mL toluene was added. The mixture was then cooled to room temperature. A 500 muL aliquot was evaporated to dryness and weighed (246 mg) to determine that the concentration of catalyst was 1.8M. [0523] 8-Benzyloxy 5-(2-bromoacetyl)-1H-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 mL) was added followed by the catalyst described above (1.8 M in toluene, 15 mL, 27 mmol). The suspension was cooled to -10+5 C. in an ice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 h. The reaction was then stirred an additional 45 min at -10 C. and then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under vacuum to give the title compound (72.5 g, 196 mmol, 81% yield, 95% ee, 95% pure by HPLC).
	In toluene; at 20℃; for 0.5h;	Chem., 1991, 56, 751-762, a catalyst was prepared as follows. (R)-(+)-alpha,alpha-Diphenylprolinol (10.0 g, 39 mmol) and trimethylboroxine (3.7 ML, 26 mmol) were combined in toluene (200 ML) and stirred at room temperature for 30 min.The mixture was placed in a 150 C. oil bath and 150 ML liquid was distilled away.toluene (50 MtL) was added, and another 50 ML of distillate was collected.Another portion of toluene (50 ML) was added and a further 50 ML of distillate was collected.A 1.00 ML aliquot of the material remaining in the pot was evaporated to dryness and weighed (241.5 mg) to determine that the concentration of catalyst was 0.87 M. 5-(2-Bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R) (30.0 g, 81 mmol) was suspended in, tetrahydrofuran (1.2 L) under a nitrogen atmosphere and the catalyst from above (13 ML, 11 mmol) was added.The suspension was cooled to -5 C. in an ice/isopropanol bath and borane (1.0 M in THF, 97 ML, 97 mmol) was added over 3 h.The reaction was stirred an additional 45 min at -5 C., then methanol (200 ML) was added slowly.The mixture was concentrated under vacuum to give 5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-quinolinone (FF). f.Synthesis of 5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-quinolinone (HH)

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2002,vol. 45,p. 145 - 155
[2]Patent: US2004/242622,2004,A1 .Location in patent: Page 30
[3]Patent: US2003/229058,2003,A1 .Location in patent: Page 48; 49

2
[ 77-78-1 ]
[ 112022-83-0 ]
[ 144119-12-0 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 2123 - 2125

3
[ 13061-96-6 ]
[ 22348-32-9 ]
[ 112022-83-0 ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3769 - 3771
[2]Chemistry Letters,2017,vol. 46,p. 740 - 743

4
[ 112022-83-0 ]
borane complex of (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dimethylsulfide borane complex; In toluene; at 20℃; for 2h;	Example 1: (S)- (-)-DECANOIC acid 1-(4-{3-14-(6-FLUORO-BENZOLD] ISOXAZOLE"3-YL)-PIPERIDINE-1-YL]" PROPOXY}-3-METHOXY-PHENYL)-ETHYL ester; a) 200 ml of a solution of (3AR)-1-METHYL-3, 3-diphenyl-tetrahydro-pyrrolo [1,2- c] [1,3, 2] oxazaborole (1 M in TOLUENE) is stirred at room temperature under nitrogen. 1.2 equivalent borane-dimethylsulfide complex is added with a syringe. The solution is stirred for 2 further hours at room temperature. The borane complex is then crystallised by addition of 4 vol dry hexane and cooling TO-12C for 1.5 hour. The product is isolated by filtration in a sintered glass funnel and dried in vacuum at 40C. The boran complex of (3AR)-1-METHYL-3, 3-diphenyl-tetrahydro-pyrrolo [1, 2-C] [1,3, 2] OXAZABOROLE is obtained (white crystals).

Reference： [1]Patent: WO2005/30763,2005,A1 .Location in patent: Page/Page column 7

5
[ 191330-56-0 ]
[ 112022-83-0 ]
[ 163222-32-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 mL), was added (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2] oxazaborole (120 mg, 0.43 mmol) and the mixture was cooled to -20 C. After 5 min, borohydride-dimethylsulfide complex (2M in THF, 0.85 mL, 1.7 mmol) was added dropwise over 0.5 h. After a total of 1.5 h, CH3OH was added followed by HCl (1 N) and the reaction mixture was extracted with EtOAc to obtain 1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-(phenylmethoxy)phenyl]-2-azetidinone (compound 6A-1) as an oil. 1H in CDCl3 d H3=4.68. J=2.3 Hz. Cl (M+H) 500. Use of (S)-tetra-hydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2] oxazaborole gives the corresponding 3(R)-hydroxypropyl azetidinone (compound 6B-1). 1H in CDCl3 d H3=4.69. J=2.3 Hz. Cl (M+H) 500. To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 mL), was added 10% Pd/C (0.03 g) and the reaction mixture was stirred under a pressure (60 psi) of H2 gas for 16 h. The reaction mixture was filtered and the solvent was concentrated to obtain compound 6A. Mp 164-166 C.; Cl (M+H) 410. [alpha]D25=28.1 (c 3, CH3H). Elemental analysis calc'd for C24H21F2NO3: C, 70.41; H, 5.17; N, 3.42; found C, 70.25; H, 5.19; N, 3.54. Similarly treat compound 6B-1 to obtain compound 6B. Mp 129.5-132.5 C.; Cl (M+H) 410. Elemental analysis calc'd for C24H21F2NO3: C, 70.41; H, 5.17; N, 3.42; found C, 70.30; H, 5.14; N, 3.52. Step 6' (Alternative): To a solution of the product of Step 5 (0.14 g, 0.3 mmol) in ethanol (2 mL), was added 10% Pd/C (0.03 g) and the reaction was stirred under a pressure (60 psi) of H2 gas for 16 h. The reaction mixture was filtered and the solvent was concentrated to afford a 1:1 mixture of compounds 6A and 6B.

Reference： [1]Patent: US2006/69080,2006,A1 .Location in patent: Page/Page column 27

6
[ 357405-87-9 ]
[ 112022-83-0 ]
[ 357405-40-4 ]

Yield	Reaction Conditions	Operation in experiment
13%	With borane; In tetrahydrofuran; methanol; toluene;	a (S)-alpha-(2-Chloroethyl)-5-isoxazolemethanol Borane (18 ml, 1M in tetrahydrofuran) was added to a solution of (3aR)-tetrahydro-1-methyl-3,3-diphenyl-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (1.3 ml, 1M in toluene) in tetrahydrofuran (10 ml) at -10 C. A solution of 3-chloro-1-(3-isoxazolyl)-1-propanone (Example 66(b)) (6 g, 37.6 mmol) in tetrahydrofuran (12 ml) was added slowly and then stirred at -10 C. to 20 C. for 18 h. Methanol was added and the solution was evaporated and the residue azeotroped with methanol. Purification by chromatography on silica eluding with petrol-ether gave the sub-title compound as a colourless oil (774 mg, 13%). MS APCI+ve m/z 162 [(M+H)+].

Reference： [1]Patent: US2003/158185,2003,A1

7
[ 492471-65-5 ]
[ 112022-83-0 ]
[ 492471-64-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; toluene;	Step 1 {4-[(R)-2-((E)-(S)-3-Hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-butoxy}-acetic Acid Methyl Ester A solution of the {4-[(R)-2-Oxo-5-((E)-3-oxo-oct-1-enyl)-pyrrolidin-1-yl]-butoxy}-acetic acid methyl ester prepared as in Example 1 (250 mg, 0.71 mmol) in 10 mL of anhydrous toluene was added dropwise to a -26 C. solution of (R)-2-methyl-CBS-oxazaborolidine (Aldrich, 1 M in toluene, 0.35 mL) and borane-methyl sulfide complex (10 M, 0.07 mL). The reaction was stirred under nitrogen for 7 hours at -26 C. and then a solution of hydrochloric acid in methanol (2 M, 1-2 mL) was added. The solution was warmed to room temperature and the solvents were removed via reduced pressure. The crude residue was purified via silica gel chromatography yielding 11 mg of {4-[(R)-2-((E)-(S)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-butoxy}-acetic acid methyl ester as an oil. This was taken directly on to the next step.

Reference： [1]Patent: US2003/64964,2003,A1

8
[ 492471-48-4 ]
[ 112022-83-0 ]
4-[(2-{(2R)-2-[(1E,3S)-3-Hydroxyoct-1-enyl]-5-oxopyrrolidin-1-yl}-ethyl)thio] Butanoic Acid Methyl Ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; toluene;	Step 4 4-[(2-{(2R)-2-[(1E,3S)-3-Hydroxyoct-1-enyl]-5-oxopyrrolidin-1-yl}-ethyl)thio] Butanoic Acid Methyl Ester A solution of methyl 4-[(2-{(5R)-2-oxo-5-[(1E)-3-oxooct-1-enyl] pyrrolidin-1-yl}ethyl)thio]-butanoate (0.039 g, 0.1 mmol) in 2 mL of anhydrous toluene was added dropwise to a -30 C. solution of (R)-2-methyl-CBS-oxazaborolidine (1 M in toluene, 0.05 mL, 0.05 mmol) and borane-methyl sulfide complex (10 M, 0.01 mL, 0.1 mmol). The reaction was stirred for 7 hours at -30 C. and then a solution of hydrochloric acid in methanol (2 M, 1-2 mL) was added. The solution was warmed to room temperature and the solvents were removed via reduced pressure. The crude residue was purified via chromatography yielding 11 mg of 4-[(2-{(2R)-2-[(1E,3S)-3-hydroxyoct-1-enyl]-5-oxopyrrolidin-1-yl}ethyl)thio] butanoic acid methyl ester as an oil. This was taken directly on to the next step.

Reference： [1]Patent: US2003/64964,2003,A1

Yield	Reaction Conditions	Operation in experiment
89%		EXAMPLE 107 (1S)-2-Bromo-1-[3-(3,4-dichlorophenyl)isoxazol-5-ylmethanol The title compound was prepared from 5-(bromoacetyl)-3-(3,4-dichlorophenylisooxazole), 1M BH6.3 3/THF, and (R)-2-methyl-CBS-oxazaborolidine monohydrate in substantially the same manner as described in Example 103 and was obtained as a white solid (4.5 g, 89% yield), mp 103-104 C.; MS m/z: 335 (M+); 1H NMR (400 MHz, DMSO-d6) delta 3.76 (m, 2H), 5.05 (m, 1H), 6.50 (d, 1H), 7.17 (s, 1H), 7.90 (d, 1H), 7.92 (d, 1H), 8.34 (s, 1H).

10
7-[2S-[4-(3-Chloro-phenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl]-heptanoic acid, ethyl ester [ No CAS ]
[ 112022-83-0 ]
[ 533893-55-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; benzo[1,3,2]dioxaborole; In tetrahydrofuran; dichloromethane; ethyl acetate; toluene;	Step B: 7-{2R-[4-(3-Chloro-phenyl)-3S-hydroxy-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester. To a solution of 7-{2R-[4-(3-chloro-phenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (2.1 g, 5.0 mmol) in anhydrous CH2Cl2 (200 mL) was added (R)-2-methyl-CBS-oxazaborolidine (1M in toluene, 5 mL, 5 mmol) and the solution was cooled to -45 C. The reaction mixture was stirred for 20 minutes and catecholborane (1M in THF, 15 mL, 15 mmol) was added. The reaction mixture was stirred for 18 h at -45 C. Aqueous HCl (1N, 100 mL) was added and the reaction mixture was stirred at room temperature for 18 h. The acidic aqueous layer was separated and the organic solution was washed with ice-cold 1N NaOH (2) followed by brine (1). The organic solution was dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (1:1 EtOAc:hexanes to 80% EtOAc in hexanes) provided 7-{2R -[4-(3-chloro-phenyl)-3S-hydroxy-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (800 mg) as an approximate 6:1 mixture of 3S:3R alcohol diastereomers by 1H NMR. 1H NMR (CDCl3) delta7.23-7.17 (m, 3H), 7.06 (m, 1H), 5.67 (dd, 1H), 5.46 (dd, 1H), 4.37 (m, 1H), 4.08 (q, 2H), 4.00 (m, 1H), 3.44 (m, 1H), 2.80 (m, 2H), 2.67 (m, 1H), 2.41-2.12 (m, 5H), 1.70-1.20 (m, 13H); MS 422.3 (M+1).

Reference： [1]Patent: US2001/47105,2001,A1

11
7-{2-oxo-5R-[3-oxo-4-(3-trifluoromethyl-phenyl)-but-1-enyl]-pyrrolidin-1-yl}-heptanoic acid ethyl ester [ No CAS ]
[ 112022-83-0 ]
7-{2R-[3S-hydroxy-4-(3-trifluoromethyl-phenyl)-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; benzo[1,3,2]dioxaborole; In tetrahydrofuran; methanol; dichloromethane; ethyl acetate; toluene;	Step B: 7-{2R-[3S-Hydroxy-4-(3-trifluoromethyl-phenyl)-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester. To a solution of 7-{2-oxo-5R-[3-oxo-4-(3-trifluoromethyl-phenyl)-but-1-enyl]-pyrrolidin-1-yl}-heptanoic acid ethyl ester (1.5 g, 3.31 mmol) and (R)-2-methyl-CBS-oxazaborolidine (1M in toluene, 0.5 mL, 0.5 mmol) in CH2Cl2 (100 mL) at -45 C. was added catecholborane (1M in THF, 9.9 mL, 9.9 mmol) dropwise. The solution was stirred for 24 h at -45 C. and 1N HCl was added. The reaction mixture was stirred at room temperature for 1 h and the layers were separated. The aqueous solution was washed with CH2Cl2 (2*) and the combined organic layers were washed consecutively with ice-cold 0.5N NaOH and brine (two times). The organic solution was dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (50% EtOAc in hexanes to 60% EtOAc in hexanes to 80% EtOAc in hexanes to EtOAc to 5% MeOH in CH2Cl2) provided 7-{2R-[3S-hydroxy-4-(3-trifluoromethyl-phenyl)-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (1.23 g) as an approximate 5.5:1 mixture of 3S:3R alcohol diastereomers by HPLC analysis. 1H NMR (CDCl3) delta7.51-7.35 (m, 4H), 5.72 (dd, 1H), 5.50 (dd, 1H), 4.44 (m, 1H), 4.09 (q, 2H), 4.01 (m, 1H), 3.44 (m, 1H), 2.90 (d, 2H), 2.71 (m, 1H), 2.37-2.12 (m, 5H), 1.70-1.21 (m, 13H); MS 456.3 (M+1), 454.3 (M-1).

Reference： [1]Patent: US2001/47105,2001,A1

12
7-{2R-[4-(3-chloro-phenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile [ No CAS ]
[ 112022-83-0 ]
7-{2R-[3S-hydroxy-4-(3-chloro-phenyl)-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; benzo[1,3,2]dioxaborole; In tetrahydrofuran; methanol; dichloromethane; toluene;	Step A: 7-{2R-[3S-hydroxy-4-(3-chloro-phenyl)-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile. To a solution of 7-{2-oxo-5R-[3-oxo-4-(3-chloro-phenyl)-but-1-enyl]-pyrrolidin-1-yl}-heptanenitrile (1.62 g, 4.34 mmol) in CH2Cl2 (200 mL) at -45 C. was added (R)-2-methyl-CBS-oxazaborolidine (1M in toluene, 1.3 mL, 1.3 mmol). After stirring for 20 minutes, catecholborane (1M in THF, 13 mL, 13 mmol) was added dropwise. The reaction was stirred at -45 C. for 16 h and 1N HCl was added. The mixture was warmed to room temperature and the layers were separated. The organic solution was washed with cold 1N NaOH (3 times). The organic solution was washed sequentially with 1N HCl, water, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by medium pressure chromatography (1:1 hexanes:EtOAc to 20% MeOH in CH2Cl2) provided 7-{2R-[3S-hydroxy-4-(3-chloro-phenyl)-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (536 mg) as an 8.2:1 mixture of 3S:2R alcohol by HPLC. 1H NMR (CDCl3) delta7.24-7.17 (m, 3H), 7.07 (m, 1H), 5.69 (dd, 1H), 5.46 (dd, 1H), 4.40 (m, 1H), 4.01 (m, 1H), 3.46 (m, 1H), 2.81 (m, 2H), 2.68 (m, 1H), 2.42-2.28 (m, 4H), 2.20 (m, 1H), 1.73-1.59 (m, 4H), 1.42 (m, 4H), 1.25 (m, 2H); MS 375 (M+1).

Reference： [1]Patent: US2001/47105,2001,A1

13
7-{2R-[4-(3-methoxymethyl-phenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester [ No CAS ]
[ 112022-83-0 ]
7-{2R-[3S-hydroxy-4-(3-methoxymethyl-phenyl)-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; benzo[1,3,2]dioxaborole; In tetrahydrofuran; methanol; dichloromethane; toluene;	Step C: 7-{2R-[3S-Hydroxy-4-(3-methoxymethyl-phenyl)-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester. To a solution of 7-{2R-[4-(3-methoxymethyl-phenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (1.40 g, 3.26 mmol) in anhydrous CH2Cl2 (200 mL) was added (R)-2-methyl-CBS-oxazaborolidine (1M in toluene, 0.49 mL, 0.49 mmol) and the solution was cooled to -45 C. The reaction mixture was stirred for 20 minutes and catecholborane (1M in THF, 9.8 mL, 9.8 mmol) was added. The reaction mixture was stirred for 24 h at -45 C and THF (100 mL) and HCl (1N, 100 mL) were added. The reaction mixture was stirred at room temperature for 24 h and at 40-45 C. for 1.5 h. The solution was diluted with CH2Cl2 and water and the layers were separated. The organic solution was cooled to 0 C. and was washed with ice-cold NaOH (0.5N) followed by brine. The organic solution was again washed with ice-cold NaOH (0.5N) followed by brine and was dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography eluding with a solvent gradient (5:1 hexanes:EtOAc to 2:1 hexanes:EtOAc to 1:1 hexanes:EtOAc to EtOAc to 2% MeOH in CH2Cl2) provided 7-{2R-[3S-hydroxy-4-(3-methoxymethyl-phenyl)-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (1.2 g) as an approximate 12:1 mixture of 3S:3R alcohol diasteromers by HPLC analysis. 1H NMR (CDCl3) (selected peaks) delta7.26-7.07 (m, 4H), 5.67 (m, 1H), 5.43 (m, 1H), 4.39 (s, 2H), 4.36 (m, 1H), 4.06 (q, 2H), 3.98 (m, 1H), 3.41 (m, 1H), 3.35 (s, 3H); MS 432.3 (M+1), 430.3 (M-1).