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[ CAS No. 53562-86-0 ] {[proInfo.proName]}

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Chemical Structure| 53562-86-0
Chemical Structure| 53562-86-0
Structure of 53562-86-0 * Storage: {[proInfo.prStorage]}
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Product Details of [ 53562-86-0 ]

CAS No. :53562-86-0 MDL No. :MFCD00064461
Formula : C5H10O3 Boiling Point : -
Linear Structure Formula :- InChI Key :LDLDJEAVRNAEBW-BYPYZUCNSA-N
M.W : 118.13 Pubchem ID :6950307
Synonyms :
(S)-Methyl 3-hydroxybutanoate

Calculated chemistry of [ 53562-86-0 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.8
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 28.6
TPSA : 46.53 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.16 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.62
Log Po/w (XLOGP3) : -0.2
Log Po/w (WLOGP) : -0.07
Log Po/w (MLOGP) : 0.01
Log Po/w (SILICOS-IT) : 0.02
Consensus Log Po/w : 0.28

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.25
Solubility : 66.7 mg/ml ; 0.564 mol/l
Class : Very soluble
Log S (Ali) : -0.32
Solubility : 56.4 mg/ml ; 0.478 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.17
Solubility : 79.9 mg/ml ; 0.676 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.78

Safety of [ 53562-86-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P312-P332+P313-P337+P313-P403+P233-P405-P501 UN#:N/A
Hazard Statements:H302+H312-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 53562-86-0 ]

* 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.

  • Downstream synthetic route of [ 53562-86-0 ]

[ 53562-86-0 ] Synthesis Path-Downstream   1~85

  • 2
  • [ 3756-30-7 ]
  • [ 53562-86-0 ]
  • [ 123408-35-5 ]
YieldReaction ConditionsOperation in experiment
80%
  • 3
  • [ 540-88-5 ]
  • [ 53562-86-0 ]
  • (+)-(5S)-hydroxy-5-oxo-3-hexanoate de tert-butyle [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With lithium diisopropyl amide In tetrahydrofuran at -78 - -15℃;
93% Stage #1: acetic acid tert-butyl ester With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.333333h; Stage #2: (S)-3-hydroxybutyric acid methyl ester In tetrahydrofuran at -50 - -15℃;
87% Stage #1: acetic acid tert-butyl ester With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.333333h; Stage #2: (S)-3-hydroxybutyric acid methyl ester In tetrahydrofuran at -50℃; for 2h;
With lithium diisopropyl amide
With lithium diisopropyl amide In tetrahydrofuran

  • 4
  • [ 53562-86-0 ]
  • [ 358-23-6 ]
  • [ 112424-25-6 ]
YieldReaction ConditionsOperation in experiment
87% With pyridine In dichloromethane at 40℃; for 2h;
  • 5
  • [ 53562-86-0 ]
  • [ 20445-31-2 ]
  • [ 76904-97-7 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide In dichloromethane for 20h; Ambient temperature;
  • 6
  • [ 53562-86-0 ]
  • [ 80522-42-5 ]
  • [ 126249-06-7 ]
YieldReaction ConditionsOperation in experiment
With 2,6-dimethylpyridine
With 2,6-dimethylpyridine In dichloromethane at 0 - 25℃; for 4h; Inert atmosphere;
  • 7
  • [ 53562-86-0 ]
  • [ 20445-33-4 ]
  • methyl (3S)-3-<(S)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl>butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
21 mg With pyridine In tetrachloromethane Ambient temperature;
  • 8
  • [ 53562-86-0 ]
  • [ 39637-99-5 ]
  • [ 76904-97-7 ]
YieldReaction ConditionsOperation in experiment
20 mg With pyridine In tetrachloromethane Ambient temperature;
  • 9
  • [ 53562-86-0 ]
  • [ 71939-50-9 ]
  • [ 82596-30-3 ]
  • [ 71963-77-4 ]
  • [ 119946-74-6 ]
  • 10
  • [ 53562-86-0 ]
  • [ 122716-72-7 ]
  • (R)-3-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-2-((S)-1-hydroxy-ethyl)-pentanoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With lithium diisopropyl amide In tetrahydrofuran for 2h; -70 gradC to 0 gradC;
  • 14
  • [ 53562-86-0 ]
  • (R)-1,1'-binaphthalene-2,2'-diyl phosphoric acid chloride [ No CAS ]
  • (S)-3-(4-Oxo-3,5-dioxa-4λ5-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yloxy)-butyric acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-methyl-1H-imidazole; dmap In dichloromethane Ambient temperature;
  • 15
  • [ 53562-86-0 ]
  • (S)-1,1′-binaphthyl-2,2′-diyl phosphorochloridate [ No CAS ]
  • (S)-3-(4-Oxo-3,5-dioxa-4λ5-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yloxy)-butyric acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-methyl-1H-imidazole; dmap In dichloromethane Ambient temperature;
  • 16
  • [ 133268-19-6 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
85% With hydrogen; triethylamine In methanol for 4h;
  • 17
  • [ 67-56-1 ]
  • [ 105-45-3 ]
  • [ 53562-86-0 ]
  • [ 29267-46-7 ]
YieldReaction ConditionsOperation in experiment
With {RuCl((R)-2,2-bis(diphenylphosphino)-1,1'-binaphthyl)(phenyl)}Cl; hydrogen In water at 17℃; for 44h;
  • 18
  • [ 105-45-3 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
100% With <Ru((S)-(-)-BINAP> cat; hydrogen In methanol; dichloromethane at 25℃; for 48h;
100% With (S)-BiphempRuBr2; hydrogen In methanol at 80℃; for 1h;
100% With hydrogen In methanol at 100℃; for 1h;
100% With hydrogen In methanol at 50℃; for 12h;
100% With ruthenium trichloride; hydrogen; (S)-(-)-(6,6’-dimethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) In methanol at 50℃; for 17h;
100% With 2,6-diisocyanatotoluene copolymer; chiral diamine; hydrogen In methanol at 50℃; for 14h;
99% In methanol a a) a) Hydrogenation of methyl acetoacetate To the resulting reddish brown solid of RuCl2(S-4)(DMF)2was added a solution of methyl acetoacetate (7.3 g, 63 mmol) in degassed methanol (40 ml) and stirred for 5 min. Then the solution was transferred to 125 ml stainless steel autoclave and kept 1h at 100°C and under hydrogen (100 atm) and then 10 h at room temperature and same pressure. After the excess hydrogen had been blown off, the apparatus was disassembled. The content was concentrated. Distillation (110°C, 46 mmHg) afforded methyl (S)-3-hydroxybutanoate (7.22 g, 98%, [α]D= - 50.5 c= 1.4, [α]546= - 58.3 c= 1.4 in CHCl3), in 99% ee assayed as MTPA ester.
99.5% With hydrogen In methanol at 80℃; for 10h; enantioselective reaction;
95% With hydrogen In methanol at 24℃; for 40h;
94% With hydrogen In methanol at 25℃; for 40h;
94% With hydrogen In methanol at 70℃; for 4h;
91.5% With hydrogen In methanol at 85℃; for 60h;
83% With Vigna unguiculata powder In water; isopropyl alcohol at 30℃; for 48h; optical yield given as %ee; enantioselective reaction;
80% With hydrogen for 48h; Ambient temperature;
80% With hydrogen for 48h; Ambient temperature;
74% With Saccharomyces cerevisiae at 30℃; for 24h; aq. buffer; optical yield given as %ee; enantioselective reaction;
64% With glucose-6-phosphate dehydrogenase; α-D-glucose 6-phosphate; bakers' yeast; NADPH In water at 30℃; for 5h;
64% With phosphate buffer; Saccharomyces cerevisiae carbonyl reductase; nicotinamide adenine dinucleotide phosphate In water at 30℃;
57% With yeast Saccharomyces cerevisiae; water In Petroleum ether for 24h; Ambient temperature;
57% With D-glucose; Escherichia coli BL21(DE3) expressing SCR and GDH enzymes; nicotinamide adenine dinucleotide phosphate In phosphate buffer
35% With Escherichia coli strain expressing Gre3p; isopropyl β-D-thiogalactopyranoside at 20℃;
18% With 2,4-Dichlorophenoxyacetic acid; Sucrose Nicotiana tabacum cells immobilized with calcium alginate;
18% With 2,4-Dichlorophenoxyacetic acid; Sucrose at 25℃; Nicotiana tabacum cells immobilized with calcium alginate; var. keto esters; var. incubation time;
13% With D-glucose; tris hydrochloride at 30℃; for 48h; β-keto ester reductase L-1, NADPH, GDH;
With glucose-6-phosphate dehydrogenase; α-D-glucose 6-phosphate; bakers' yeast; NADP In water at 30℃;
99 % Chromat. With hydrogen In methanol at 30℃; for 40h;
With tartaric acid-Raney Ni-NaBr; hydrogen In acetic acid at 100℃; for 1h;
With hydrogen In methanol at 30℃; for 48h;
95 % Chromat. With triethanolamine-NaOH buffer; NAD; sodium formate Ambient temperature; carbonyl reductase from Candida parapsilosis (CPRC), formate dehydrogenase (FHD), pH 7.5;
With hydrogen In methanol at 50℃; for 48h;
With immobilized Nicotiana tabacum cells at 25℃; for 192h;
With D-glucose 6-phosphate; MES buffer pH 6.0 at 35℃; for 12h; α-acetoxy ketone reductase from bakers' yeast, glucose 6-phosphate dehydrogenase, NADPH;
With 1,2-bis[(R,R)-2,5-diisopropylphospholano]ethane-RuBr2; hydrogen In methanol; water at 35℃; for 20h;
With dried Baker's yeast In water; Petroleum ether for 18h; Yield given;
99 % Chromat. With (+/-)-2-pentanol; 2-(N-morpholino)ethanesulfonic acid buffer; NAD at 30℃; for 24h; acetone powder of Geotrichum candidum IFO4597(APG4);
With Saline; Bacillus sp. DSM 457; glycerol at 37℃; for 20h; Yield given;
With RuCl2<(S)-bis(3-dehydroxy-3-diphenylphosphinoequilenin-4-yl)>(DMF)2; hydrogen at 100℃; for 1h;
With 3-deoxyglucosone reductase from dog adrenal; NADP; NADPH In water
With 2-(N-morpholino)ethanesulfonic acidbuffer; NAD; isopropyl alcohol at 30℃; for 20h; acetone powder of Geotrichum candidum; Yield given;
With hydrogen In methanol at 70℃; for 2h;
With hydrogen bromide; hydrogen; (S)-5',6'-benzo-6-methoxy-2,2'-bis(diphenylphosphanyl)biphenyl In methanol at 50℃; for 3h;
With ammonium acetate; bakers' yeast; Sucrose In phosphate buffer at 20℃;
With hydrogen In methanol at 50℃; for 24h;
With (S)-BINAP derivative; hydrogen In 1,4-dioxane; ethanol; N,N-dimethyl-formamide at 60℃; for 10h;
100 % Chromat. With hydrogen In dichloromethane at 70℃; for 24h;
With immobilized baker's yeast; Sucrose In glycerol at 37℃; for 48h;
With hydrogen In methanol; dichloromethane at 70℃; for 24h;
76 % Chromat. With D-glucose; engineered yeast strain 2B(pSRG41); Tris-Cl buffer at 30℃;
With hydrogen In ethanol; dichloromethane at 50℃; for 20h;
With hydrogen In methanol at 70℃; for 2h;
With 1,4-dihydronicotinamide adenine dinucleotide; (S)-alcohol dehydrogenase; formate dehydrogenase from C. boidini; Rhodococcus erythropolis (E.coli) In phosphate buffer Enzymatic reaction;
With 1,4-dihydronicotinamide adenine dinucleotide; (S)-alcohol dehydrogenase from Rhodococcus erythropolis In phosphate buffer at 30℃;
94.3 % ee With hydrogen In methanol; water at 25℃; for 16h;
13 g With sodium tetrahydroborate In methanol at 20℃; for 2h;
90.7 % ee With hydrogen In methanol at 20℃; for 6h; 18 Complex 5B-a from Example 1 (2.6 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed methanol (2 mL) was added and the mixture was stirred for 15 minutes. Methyl acetoacetate (54 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed methanol was added and was washed in with 1.0 mL of argon-degassed methanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times. Assay of the product solution by chiral GC showed 100% conversion to methyl (S)-3-hydroxybutyrate with 90.7% ee. Chiral GC [30 m×0.25 mm Cyclosil-B (J&W Scientific), 0.25 μm film thickness, 100° C. isothermal]: tR=6.29 min (methyl acetoacetate), tR=6.54 min [methyl (S)-3-hydroxybutyrate], tR=6.71 min [methyl (R)-3-hydroxybutyrate].
93 % ee With hydrogen In ethanol; dichloromethane at 60℃; for 20h; [Ru(benzene)Cl2]2 (N) (16 mg, 0.032 mmol) and a diphosphonite (0.067 mmol) were introduced into a 25 ml Schlenk tube. The tube was purged three times with argon before dry dimethylformamide (DMF) (3 ml) was added. The resulting mixture was heated to 100° C. for 30 minutes and then cooled to 60° C. The solvent was removed under reduced pressure, and the catalyst was obtained as a pale green-yellow solid. This catalyst was dissolved in dry dichloromethane (8 ml) and distributed uniformly between 8 vials (in each case 1 ml), which had already been purged three times with argon. A ketone, such as a β-keto ester (III) (0.8 mmol), was introduced into each vessel, then in each case 3 ml of ethanol were added. These were then transferred to a high-pressure autoclave. Once it had been purged three times with H2, the autoclave was adjusted to a pressure 60 bar with H2, and the reactions were stirred magnetically at 60° C. over 20 h. The autoclave was subsequently cooled to room temperature and H2 was cautiously discharged. Samples were taken from each reaction solution and put through a small amount of silica gel before the GC analysis in order to determine the conversions and ee values. The absolute configuration was determined in comparison to known compounds described in the literature.
>= 99 % ee With hydrogen In methanol at 100℃; for 2 - 6h; 7; 8; 9; 10 Example 7; Asymmetric Hydrogenation of Methyl Acetoacetate; Example 7 describes a method for asymmetrically hydrogenating methyl acetoacetate to form S-(+)-methl-3-hydroxyl-buterate. 4.0 g SiO2 immobilized Ru (s-BINAP)Cl2 catalyst manufactured using the method of Example 1 and 3.32 g methyl acetoacetate were placed in 300 ml stainless steel autoclave equipped with a mechanically stirring blade, a pressure gauge, and a gas inlet tube attached to a hydrogen source. Air present in the autoclave was replaced by nitrogen. 100 ml methanol was added to the autoclave under a stream of nitrogen. The mixture was degassed by three vacuum-filling with nitrogen cycles. Thereafter, the autoclave was charged with about 30 psi nitrogen and then heated to 100° C. When the temperature stabilized, the vessel was pressurized to 1060 psi with hydrogen. The reaction mixture was vigorously stirred for 2 hr at 100° C. The conversion of methyl acetoacetate to S-(+)-methl-3-hydroxyl-buterate was determined by HPLC (column, AGP 150×40 mm; eluent, 10:90 2-propanol-H2O with PH 5.9; temp, 27.8° C.; flow rate, 0.3 ml/min. The tR of S-(+)-methyl-3-hydroxyl-butyrate was 5.40 min (84.23%), the tR of R-isomer, 4.71 min. (<0.5%), and the tR of methyl acetoacetate was 4.76 min. (15.77%). The conversion was 84.23% with >99% enantiomeric excess.; Example 8; Asymmetric Hydrogenation of Methyl Acetoacetate; Example 8 describes a method for asymmetrically hydrogenating methyl acetoacetate to form S-(+)-methl-3-hydroxyl-buterate using a recycled catalyst. Catalyst used in the method of Example 7 was obtained by filtration and used in a second run according to the method of Example 7. The conversion determined by HPLC was 96.45% with >99% enantiomeric excess.; Example 9; Asymmetric Hydrogenation of Methyl Acetoacetate; Example 9 describes a method for asymmetrically hydrogenating methyl acetoacetate to form S-(+)-methl-3-hydroxyl-buterate. The procedure was carried out similar to the procedure describe in Example 7 except that the immobilized catalyst of Example 2 was used rather than the catalyst from Example 1. The reaction was carried out for 4 hr using 4.0 g of the immobilized Ru(s-BINAP)Cl2 catalyst from Example 2. The conversion determined by HPLC was 83.39% with >99% enantiomeric excess.; Example 10; Asymmetric Hydrogenation of Methyl Acetoacetate; Example 10 describes a method for asymmetrically hydrogenating methyl acetoacetate to form S-(+)-methl-3-hydroxyl-buterate using a recycled catalyst. Catalyst used in the method of Example 9 was obtained by filtration and used in a second run, and then in a subsequent third run, and subsequent fourth run. All were subsequent runs were performed by filtering the catalyst from the prior reaction and reusing the catalyst according to the method of Example 9, except that the reaction time was 6 hr. The product was analyzed by HPLC and determined to be 95.86% conversion and 99% ee for the second run, 95.98% conversion and 99% ee for the third run, and 95.59% conversion and 99% ee for the forth run.
With dichloro(benzene)ruthenium(II) dimer; C49H52O2P2; hydrogen In methanol at 80℃; for 12h; optical yield given as %ee; enantioselective reaction;
> 99 % ee With hydrogen In methanol at 50℃; for 24h; 6.b b) with ruthenium trichloride The substrate to be hydrogenated (1 mmol), dissolved in 2 ml of hydrogenation solvent, is added to 2.1 mg of ruthenium trichloride and 1.1 equivalents of compound (I). The hydrogenation is performed in an autoclave for the necessary time at the desired pressure and temperature.
99 % ee With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); hydrogen In methanol at 60℃; for 20h; General procedure for Ru-catalysed asymmetric hydrogenation of MAA in IL/MeOH systems and for catalyst recycling General procedure: Typically, the preceding catalysts 6-Ru (0.0031 mmol) or 7-Ru(0.0031 mmol) were dissolved in IL/MeOH (IL: 1 g, MeOH: 1 mL)under an argon atmosphere. The MAA (36 mg, 0.31 mmol) wereadded to the solution of catalyst. Next, the reaction mixture wastransferred to a 60 mL autoclave. The hydrogenation was carriedout under 4 MPa pressure of hydrogen at 60 ◦C for 20 h. After releasingthe hydrogen, the reaction mixture was transferred to a Schlenktube under an argon atmosphere. Next the MeOH was removedunder reduced pressure and ether was added to extract the product(1 mL×2). The top solvent layer was removed by a syringe forGC analysis, and the new substrate and MeOH was added to the ILfor next catalyst recycling
> 99.9 % ee With potassium phosphate; Candida parapsilosis aldo-keto reductase CPAR4; NADPH at 30℃; for 8h; Enzymatic reaction; enantioselective reaction; 2.7 Asymmetric reduction of carbonyl compounds General procedure: Asymmetric reductions of various carbonyl compounds by the purified enzymes were carried out at 30°C for 8h with mild shaking in a reaction mixture containing 0.1M potassium phosphate buffer (pH 6.5), 1gL-1 substrate, 10mM NADPH, and the purified enzyme of appropriate amount in a total volume of 2mL. In order to determine the absolute configuration of chiral alcohols, the reaction products were extracted with ethyl acetate or hexane and the organic layer was used for analysis. The optical purity of the reaction products were determined by chiral HPLC (HP 1100, Agilent, USA) equipped with Chiralcel OB-H column (4.6mm×250mm; Daicel Chemical Ind. Ltd., Japan) or chiral GC (7890A, Agilent, USA) equipped with FID detector and Chrompack Chirasil-Dex CB chiral capillary column (25m×0.25mm; Varian, USA) [21].
99 % ee With ruthenium trichloride; hydrogen; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine) In methanol at 25℃; for 36h; Autoclave; 15 (S)-Methyl 3-hydroxybutanoate (8) Preparations of the β-hydroxy ester 8 were carried out as described by Noyori and co-workers20 who have described the asymmetric reduction of methyl acetoacetate using a ruthenium catalyst bearing the chiral diphosphine ligand (S)-(-)-BINAP enantiomers commercially available from Aldrich Chemicals. β-hydroxyester reduction was conducted on a 30 g scale in Hasteloy steel autoclave vessels using a MeOH (30 mL) solvent. The reactions were allowed to proceed at constant H2 pressure (1500 psi) for 36 h at 25° C. Complete conversion of the methyl acetoacetate was observed and the products were simply distilled from the crude reaction mixture. Consistent with the results of Noyori et al., β-hydroxyester 8 was determined to be 99% enantiomerically pure. Rf 0.2 (petroleum ether-EtOAc, 9:1); [a]D20 19.6 (c 1.0, CHCl3). IR (KBr) νmax3424, 1735, 1440, 1379, 1296, 1175, 1087, 1007, 945, 848, 602 cm-1. 1H NMR (300 MHz, CDCl3): 4.27-4.15 (m, 1H), 3.72 (s,3H), 3.01-2.89 (br, 1H), 2.47 (dd, J=8.3, 6.8 Hz, 2H) 1.23 (d, J=6.8 Hz,3H). 13C NMR (75 MHz, CDCl3): 172.8, 63.9, 51.3, 42.6, 22.3; MS (EI): m/z=141 [M+Na]+.
With Candida parapsilosis carbonyl reductase 2 W286S; NADH In aq. buffer Enzymatic reaction;
> 99.5 %Chromat. With hydrogen In isopropyl alcohol at 50℃; for 10h; Autoclave; Glovebox; enantioselective reaction; 2.6 Catalytic process General procedure: As a typical run for asymmetric hydrogenation of β-keto esters, 0.026 g Ru/5-BINAPPOPs-1 catalyst, 0.20 g methyl acetoacetate, and 2 mL of isopropanol (ipro) were added to a 30-mL autoclave in a glove box. After the reactor was purged with H2 four times, its pressure was finally adjusted to the desired value, heated from room temperature to the reaction temperature of 50 °C, and stirred for 10 h. The catalyst was separated by centrifugation, and the product was analysed using gas chromatography (GC; Agilent 7890B gas chromatograph equipped with a flame ionization detector and a Cyclosil-B capillary column).
98.8 % ee With D-Glucose; cobalt(II); BaSDR1 reductase variant Q139G; NADH In aq. phosphate buffer at 35℃; Enzymatic reaction; enantioselective reaction;
94 % ee With hydrogen; {RuI(p-cymene)[(S)-BINAP-(SO3Na)2]I; sodium iodide In water at 60℃; for 20h; Inert atmosphere; Schlenk technique; Autoclave; enantioselective reaction; 2.6. General procedure for the Ru-catalyzed enantioselectivehydrogenation of MAA and EAA in H2O using a cationic {RuI(p-cymene)[(S)-BINAP-(SO3Na) catalyst General procedure: Under an argon atmosphere, freshly prepared {RuI(p-cymene)[(S)-BINAP-(SO3Na) catalyst in Section 2.4, 1 × 103 equivalents of MAAor EAA, 33 mg NaI (0.22 mmol) and 2 mL H2O were added to a 60 mLautoclave, and the reaction mixture was stirred at a hydrogen pressureof 4.0 MPa and 60 °C for 20 h. After the completion of the reaction, theautoclave was placed in ice water to cool to room temperature, and thepressure was released. The reaction mixture was transferred to a 20 mLSchlenk tube, and n-hexane was added for extraction (2 mL × 3). Theextract was dried with anhydrous Na2SO4 and loaded onto GC todetermine the conversion and ee value with a Lipodex A chiral capillarycolumn (25 m ×0.25 mm). The aqueous phase containing catalyst wasreplenished with fresh MAA and then transferred to the autoclave for thenext cycle. (S)-3-hydroxybutanoic acid, methyl ester. 1H NMR (500 MHz, CDCl3):δ = 4.205 (m, 1H, -CHOH-), 3.720 (s, 3H, OCH3), 2.832 (br, 1H, -OH),2.508 (m, 1H, -OHCHCHHC(O)-), 2.436 (m, 1H, -OHCHCHHC(O)-),1.235 (dd, J1 = 6.5 Hz, J2 = 1.5 Hz, 3H, CH3CHOH-); e.e. determined byGC, Lipodex A chiral capillary column, 30 °C (10 min)-1 C/min-60 °C (20 min), (S) t1 = 26.462 min, (R) t2 = 27.322 min, 94 % ee.
> 99 % ee With 2,3,4,5,6-pentahydroxy-hexanal; Bacillus megaterium glucose dehydrogenase; recombinant Hansenula polymorpha ketoreductase; nicotinamide adenine dinucleotide In aq. phosphate buffer at 37℃; for 24h; Enzymatic reaction; enantioselective reaction; Biotransformations with purified KRED General procedure: Small-scale screening reactions were carried out in 1.5 mL plastic testtubes with a total volume of 1 mL of reaction mixture containingcarbonyl substrate (20-46 mM, Table 2), glucose (0.1 M), NADP+ (1mM), KRED (0.06-4.8 mg mL-1), GDH (0.03-0.072 mg mL-1) and potassiumphosphate buffer (0.1 M, pH 6.5). Reductions were performed at37 C and 550 rpm in a thermomixer (Eppendorf, Germany) for 24 h.Reaction aliquots (50 μL) were taken during biotransformations atvarious time intervals and extracted with ethyl acetate (200 μL) by 10 sof vortexing, followed by centrifugation (13,300g, 1 min), the extractswere analysed by gas chromatography (GC).

Reference: [1]Burk; Feaster; Harlow [Tetrahedron Asymmetry, 1991, vol. 2, # 7, p. 569 - 592]
[2]Genet, J. P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart, S.; Pfister, X.; et al. [Tetrahedron Asymmetry, 1994, vol. 5, # 4, p. 675 - 690]
[3]Enev; Harre; Nickisch; Schneider; Mohr [Tetrahedron Asymmetry, 2000, vol. 11, # 8, p. 1767 - 1779]
[4]Mashima, Kazushi; Nakamura, Tomoko; Matsuo, Yutaka; Tani, Kazuhide [Journal of Organometallic Chemistry, 2000, vol. 607, # 1-2, p. 51 - 56]
[5]Madec; Pfister; Phansavath; Ratovelomanana-Vidal; Genêt [Tetrahedron, 2001, vol. 57, # 13, p. 2563 - 2568]
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  • 19
  • [ 105-45-3 ]
  • [ 53562-86-0 ]
  • [ 3976-69-0 ]
YieldReaction ConditionsOperation in experiment
100% With Ru2Cl4-(S)-(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)2*NEt3; hydrogen In methanol at 35℃; for 48h; Title compound not separated from byproducts;
100% With <((R)-(1,1'-binaphthyl-2,2'-diyl)bis(diphenylphosphine))RuCl2>2NEt3; hydrogen In methanol at 35℃; for 48h; Title compound not separated from byproducts;
95% With hydrogen In methanol at 40 - 65℃;
90% With hydrogen In methanol at 60℃; for 20h;
85% With ruthenium trichloride; hydrogen; [2R-[1(2'R*,5'R*),2a,5b]]-1,1'-(1,2-phenylene)bis[2,5-dimethylphospholane] In methanol at 80℃; for 72h; Title compound not separated from byproducts;
47% at 30℃; for 24h; Kroekera sp No. 2201 (AKU 4705) growning in 10percent glucose solution; Yields of byproduct given;
With tartaric acid-Raney Ni-NaBr; hydrogen In acetic acid at 100℃; for 1h; pH=4.0; other modified Raney Ni catalyst system;
With L-glutamic acid; hydrogen other reagents (chiral amino acids);
With L-Tartaric acid; ultrasonicated Raney nickel catalyst; hydrogen; acetic acid; sodium bromide In various solvent(s) at 100℃; for 2.5h; other methyl 3-oxoalkanoates; var. times and catalysts;
With L-Tartaric acid; Ni acetylacetonate; zeolite (Si/Al=15); hydrogen; sodium bromide In tetrahydrofuran; acetic acid other reagent, enantioselectivity of the reaction;
98 g With hydrogen Title compound not separated from byproducts;
With hydrogen Yield given. Yields of byproduct given;
With potassium hydroxide 1.) EtOH, 25 deg. C, 20 h, 2.) baker's yeast, fermentation medium, 25 deg C, 2 d; Yield given. Multistep reaction. Title compound not separated from byproducts;
With hydrogen In various solvent(s) at 60℃; for 48h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With (S,S)-SKEWPHOS-RuBr2; hydrogen In methanol at 25℃; Yield given. Yields of byproduct given;
With hydrogen In various solvent(s) at 100℃; for 2.5h; Title compound not separated from byproducts;
With hydrogen In acetic acid at 100℃; Yield given. Yields of byproduct given;
With hydrogen Yield given. Yields of byproduct given;
With hydrogen In methanol; dichloromethane at 30℃; for 40h; Yield given. Yields of byproduct given;
With L-Tartaric acid; hydrogen; acetic acid; sodium bromide In various solvent(s) at 100℃; for 2.5h; Title compound not separated from byproducts;
With hydrogen In acetic acid at 100℃; for 5h; Title compound not separated from byproducts;
With Ru<(S)-Ph,Ph-oxoProNOP>(OCOCH3)2; hydrogen In dichloromethane at 20℃; for 192h; Title compound not separated from byproducts;
With RuCl2<(R)-bis(3-dehydroxy-3-diphenylphosphinoequilenin-4-yl)>(DMF)2; hydrogen at 100℃; for 1h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With hydrogen In methanol at 30℃; for 24h;
With ammonium sulfate; potassium dihydrogenphosphate; ordinary baker's yeast; magnesium sulfate; Sucrose for 24h; Title compound not separated from byproducts;
With hydrogen In tetrahydrofuran; acetic acid at 60℃; Title compound not separated from byproducts;
With hydrogen In methanol at 80℃; for 22h; Title compound not separated from byproducts;
With sulfuric acid; hydrogen In water at 70℃; for 2h;
With ammonium hexafluorophosphate; hydrogen; (R,R)-1,3-Dicyclohexyl-1,3-propanediol cyclic sulfate In methanol at 80℃; for 20h; Title compound not separated from byproducts;
With hydrogen; sodium bromide In tetrahydrofuran at 100℃; for 5h;
With hydrogen In methanol at 50℃; for 14h;
With L-Tartaric acid; hydrogen; sodium bromide In tetrahydrofuran; acetic acid at 60℃; for 4h;
With L-Tartaric acid; hydrogen; sodium bromide In tetrahydrofuran at 100℃; for 4h; Title compound not separated from byproducts;
With chiral 1,5-diphenylphosphanylferrocene compound; hydrogen bromide; hydrogen In methanol at 50℃; for 8h;
With hydrogen; 2,3-dimethyl-1-n-propyl-imidazolium bis(trifluoromethylsulfonyl)imide In methanol at 20℃; for 22h;
With hydrogen bromide; hydrogen In methanol at 50℃; Title compound not separated from byproducts;
With hydrogen In methanol at 60℃; for 20h;
With hydrogen In methanol Title compound not separated from byproducts;
With chiral dinaphtho[2,1-c;1',2'-e]phosphepine; hydrogen bromide; hydrogen In methanol at 100℃; for 8h; Title compound not separated from byproducts;
With Rhizopus arrhizus culture In ethanol at 27℃; for 192h; Title compound not separated from byproducts;
With hydrogen; 1-butyl-3-methylimidazolium Tetrafluoroborate In methanol at 60℃; for 0.0833333h;
With (Sa)-4-F-C6H4-3H,4H,5H-dinaphtho-[2,1-c;1',2'-e]phosphepine; hydrogen In methanol at 120℃; for 1h;
With hydrogen; acetic acid In tetrahydrofuran at 99.85℃;
With sodium hydroxide; hydrogen; (R,R)-tartaric acid monosodium salt In tetrahydrofuran at 373℃;
With hydrogen In methanol at 20℃; for 20h;
With hydrogen In ethanol at 20℃; for 6h;
With hydrogen; sodium bromide In methanol at 60℃; for 1h;
With hydrogen; acetic acid at 100℃; for 17h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
reductive effect of various yeasts toward β-keto esters discussed;
With hydrogen; acetic acid at 100℃; for 17h; various commercial Ni powders/NaBr/(R,R)-tartaric acid;
With hydrogen In methanol; dichloromethane at 60℃; for 24h; Title compound not separated from byproducts.;
76.2 % ee With hydrogen In methanol at 20℃; for 6h; 26 Complex 5A-c from Example 5 (2.6 mg; 0.0025 mmol; 0.005 equiv) was placed in a reaction vessel, which was pressurized with argon and vented five times. Argon-degassed methanol (2 mL) was added and the mixture was stirred for 15 minutes. Methyl acetoacetate (54 μL; 0.5 mmol) dissolved in 2 mL of argon-degassed methanol was added and was washed in with 1.0 mL of argon-degassed methanol. The reaction mixture was pressurized with argon and vented five times and then pressurized to 20.7 barg (300 psig) with hydrogen and stirred at ambient temperature for 6 hours. The vessel was vented, then pressurized with argon and vented five times, and the solution was assayed by chiral GC to indicate 100% conversion to methyl (R)-3-hydroxybutyrate with 76.2% ee.
With hydrogen In methanol at 60℃; Title compound not separated from byproducts.;
With Hansenula sp Enzymatic reaction; optical yield given as %ee;
With Aspergillus niger Enzymatic reaction; optical yield given as %ee;
With hydrogen In methanol at 50℃; for 24h; Autoclave; optical yield given as %ee; enantioselective reaction;
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; sodium formate; (2S)-N-phenylpyrrolidine-2-carboxamide In water at 30℃; for 16h; optical yield given as %ee; enantioselective reaction;
With N,N,N,N-triethylhexylammonium hexafluorophosphate; hydrogen In methanol at 59.84℃; optical yield given as %ee;
With hydrogen In tetrahydrofuran; acetic acid at 99.84℃; for 20h; Autoclave; enantioselective reaction;
86 % ee With L-Tartaric acid; hydrogen; nickel; acetic acid; sodium bromide In tetrahydrofuran; water at 99.84℃; for 20h; Autoclave; enantioselective reaction;
80.5% ee With hydrogen In ethanol at 60℃; for 6h; Inert atmosphere; Autoclave; Overall yield = 15.3 %Chromat.; enantioselective reaction; 2.4. Catalytic hydrogenation General procedure: Catalytic hydrogenation reactions were carried out in a 50 mL autoclave equipped with a magnetic bar. The reaction temperature was controlled by an electric heater and maintained at a set temperature. All reaction temperatures were 60 ◦C, and the hydrogen pressure was set at 40 bar. Prior to use, all substrates and solvents were degassed at reduced pressure with an aspirator. Under inert atmosphere conditions, catalyst, degassed solvent, and substrate were introduced sequentially into the reactor. The reactor was connected to a hydrogenation apparatus and purged with hydrogen (3 bar) five times before stirring was initiated. The reaction was initiated by introducing hydrogen at a pressure of 40 bar. Samples were obtained at predetermined time intervals from the reaction mixture to determine the reaction rate and enantioselectivity. The products were analyzed by gas chromatography (HP 6890) using a Rtx-1701 column. Enantiomeric excess was determined by GC using a Chiraldex G-TA column.
88 % ee With L-Tartaric acid; hydrogen; nickel; acetic acid; sodium bromide In tetrahydrofuran at 99.84℃; for 20h; enantioselective reaction; Enantiodifferentiating hydrogenation with chirally modified nickel catalyst The modified catalyst was placed into an autoclave equipped with a magnetically coupled mechanical stirrer and contained a mixture of methyl acetoacetate (5 g), acetic acid (0.1 g), and THF (10 cm3). The hydrogenation reaction was run for 20 h at 373 K and an initial hydrogen pressure of 9 MPa. The hydrogenation product, methyl 3-hydroxybutyrate, was isolated from the reaction mixture by distillation. The enantioselectivity was measured by using gas-liquid chromatography (GLC). Acetylation of the reaction product for the GLC measurements was carried out by using acetyl chloride and pyridine. A portion of the acetylated sample was subjected to the chiral GLC analysis on a CP Chirasil DEX-CB column (0.25 mm x 25 m) operated at 363 K. The enantioselectivity was calculated from the peak integration ofthe corresponding enantiomer peaks. The reproducibility of the enantioselectivity was found to be within ±2%.
89 % ee With hydrogen; acetic acid In tetrahydrofuran at 99.84℃; for 20h; Autoclave; enantioselective reaction;
78.56 % ee With potassium phosphate; Candida parapsilosis aldo-keto reductase CPAR5; NADPH at 30℃; for 8h; Enzymatic reaction; enantioselective reaction; 2.7 Asymmetric reduction of carbonyl compounds General procedure: Asymmetric reductions of various carbonyl compounds by the purified enzymes were carried out at 30°C for 8h with mild shaking in a reaction mixture containing 0.1M potassium phosphate buffer (pH 6.5), 1gL-1 substrate, 10mM NADPH, and the purified enzyme of appropriate amount in a total volume of 2mL. In order to determine the absolute configuration of chiral alcohols, the reaction products were extracted with ethyl acetate or hexane and the organic layer was used for analysis. The optical purity of the reaction products were determined by chiral HPLC (HP 1100, Agilent, USA) equipped with Chiralcel OB-H column (4.6mm×250mm; Daicel Chemical Ind. Ltd., Japan) or chiral GC (7890A, Agilent, USA) equipped with FID detector and Chrompack Chirasil-Dex CB chiral capillary column (25m×0.25mm; Varian, USA) [21].
17.56 % ee With potassium phosphate; Candida parapsilosis aldo-keto reductase CPAR6; NADPH at 30℃; for 8h; Enzymatic reaction; enantioselective reaction; 2.7 Asymmetric reduction of carbonyl compounds General procedure: Asymmetric reductions of various carbonyl compounds by the purified enzymes were carried out at 30°C for 8h with mild shaking in a reaction mixture containing 0.1M potassium phosphate buffer (pH 6.5), 1gL-1 substrate, 10mM NADPH, and the purified enzyme of appropriate amount in a total volume of 2mL. In order to determine the absolute configuration of chiral alcohols, the reaction products were extracted with ethyl acetate or hexane and the organic layer was used for analysis. The optical purity of the reaction products were determined by chiral HPLC (HP 1100, Agilent, USA) equipped with Chiralcel OB-H column (4.6mm×250mm; Daicel Chemical Ind. Ltd., Japan) or chiral GC (7890A, Agilent, USA) equipped with FID detector and Chrompack Chirasil-Dex CB chiral capillary column (25m×0.25mm; Varian, USA) [21].
89 % ee With hydrogen; acetic acid In tetrahydrofuran at 110℃; for 20h; Autoclave; enantioselective reaction; General procedure: Nickel powders (5 μm) purchased from Aldrich were directly subjected to chiral modification without any pretreatment, such as hydrogen activation. The chiral modification was performed under the conditions optimized previously for this type of catalyst.26 Thus, the non-activated nickel powders (0.5 g) were immersed in an aqueous solution (50 cm3) of (R,R)-tartaric acid (0.5g) and NaBr (2.0 g) at 100 °C, the pH of which was pre-adjusted to 3.2 with an aqueous 1M NaOH solution. NaBr was added to the modification solution to block the non-enantiodifferentiating sites of tartaric acid/Ni catalyst, thus preventing the generation of racemic products.39 After immersion for 1 h, the modification solution was removed by decantation and the catalyst was successively washed once with deionized water (10 cm3), twice with methanol (25 cm3), and twice with tetrahydrofuran (THF) (10 cm3). The modified catalyst was added to a mixture of alkyl acetoacetate (43 mmol for methyl ester and 21.5 mmol for other esters), acetic acid (0.1g), and THF (10 cm3) placed in an autoclave equipped with a magnetically coupled mechanical stirrer. The hydrogenation was run for 20h at 100 or 110 °C and at a hydrogen pressure of 9MPa. The hydrogenation product, a mixture of alkyl (R)- and (S)-3-hydroxybutyrates, was isolated from the reaction mixture by distillation. The conversion was determined by gas-liquid chromatography (GLC) on a GL Science model GC-4000 equipped with a CP Chirasil DEX-CB capillary column (0.25 mm × 25 m) at 90 °C, while the enantioselectivity was determined by chiral GLC after acetylation of the reaction product using acetyl chloride and pyridine. A portion of the acetylated sample was subjected to the chiral GLC analysis on a CP Chirasil DEX-CB column (0.25 mm × 25 m) operated at 90 °C. The ee value was calculated from the peak integration of the corresponding enantiomer peaks. The reproducibility of the ee value was found to be within ±2%.
72 % ee With dichloro(benzene)ruthenium(II) dimer; hydrogen In methanol at 52℃; for 2h;
With hydrogen In tetrahydrofuran at 59.84℃; Autoclave; Overall yield = 100 %; Optical yield = 86 %ee; enantioselective reaction; Hydrogenation and Analysis of the Product The catalyst (0.4 g) and a solution of methyl acetoacetate (MAA, 2 g) in THF (20 mL) were placed in a 100 mL autoclave. Hydrogen was charged into the autoclave under the initial pressure of 10 MPa, and the autoclave was heated to 333 ± 1 K under reciprocating shaking until the end of the hydrogen uptake. Aliquots of the reaction mixture were periodically withdrawn for analysis. When MAA was hydrogenated over the modified RNi catalysts, methyl 3-hydroxybutyrate was obtained in a quantitative yield. Enantiomeric ratios of (R)- and (S)-methyl3-hydroxylbutyrates were determined by GLC equipped witha CP-Chirasil DEX CB capillary column (25 m, 0.25mm id, GL Science, Japan, flow rate: 30 cm s-1). After acetylation with acetic anhydride and pyridine, the retention times of the product (363 K) are 7.1 min for (S) and 7.5 min for (R). Enantioexcess (ee) is defined here as ee (%) = 100([R] - [S])/([R] + [S]) (1) where [R] and [S] denote the amounts of (R)- and (S)-methyl 3-hydroxylbutyrates.
87 % ee With C34H36ClIrNPS2; potassium <i>tert</i>-butylate; hydrogen In methanol at 25 - 30℃; for 8h; Autoclave; enantioselective reaction;
86 % ee With hydrogen; acetic acid In tetrahydrofuran at 59.84℃; Autoclave; enantioselective reaction; 4.4. Hydrogenation procedure13-15 General procedure: To a 100 mL autoclave, a substrate mixture of methyl acetoacetate(2.8 mmol) and 1 (2.8 mmol) or 2 (2.8 mmol) in THF(40 mL) was placed with acetic acid (0.2 mL) and a tartaric acid or malic acid-modified Raney nickel or unmodified Raney nickel catalyst (400 mg). Hydrogen was injected (10 MPa), and the autoclave was heated to 333 K. At 293 K, shaking was started to initiate the catalytic reaction. Next, 3 mL of the product mixture were withdrawn each time from the reactor at predetermined reaction times for analysis, while keeping the hydrogen pressure high.The conversion analysis of each sample was conducted by NMR. The conversion is defined here as the conversion of the substrate to total hydrogenated products, (S)- and (R)-enantiomers.
88 % ee With L-Tartaric acid; hydrogen; acetic acid; sodium bromide In tetrahydrofuran; water at 99.84℃; for 20h; Autoclave; enantioselective reaction; 2.1.1 Hydrogenation of Methyl Acetoacetate A 1.3 g sample of nickel oxide (Wako Pure ChemicalIndustries, Ltd.) was treated at 623 K for 1 h under a H2stream (30 cm3 min-1) to obtain a reduced nickel catalyst.Various salts of acetic acid or alkali bromides in 50mm3H2Oand (R,R)-tartaric acid (the amounts are statedin the text) were added to a mixture of methyl acetoacetate(5.0 g), acetic acid (0.1 g), and THF (10cm3). This substratesolution and the reduced nickel catalyst were placedin a magnetically-stirred autoclave [OM Lab-Tech Co., Ltd.(Tochigi, Japan)]. Hydrogenation was carried out under theinitial hydrogen pressure of 9MPa at 373K for 20h. Thestirring rate of the autoclave was 1130 r.p.m.
8 % ee With bis(1,5-cyclooctadiene)diiridium(I) dichloride; C37H35FeN2P; potassium <i>tert</i>-butylate; hydrogen In methanol at 20℃; for 12h; Autoclave; Glovebox; Overall yield = 90 %; enantioselective reaction;
45 % ee With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); 2′-(tert-butylmethylphosphanyl)biphenyl-2-yl camphanate; hydrogen bromide; hydrogen In methanol at 80℃; for 16h; Autoclave; Overall yield = 61.5 %; enantioselective reaction;
84.1 % ee With hydrogen In tetrahydrofuran at 50℃; for 10h; Overall yield = > 99.5 %Chromat.; enantioselective reaction;
32 % ee With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (SC,SC,RFC)-1-(diphenylphosphino)-2-[1-N-((4S)-4-tert-butyl-2-oxazolinyl-2-ylmethyl)ethyl]ferrocene; potassium <i>tert</i>-butylate; hydrogen In methanol at 20℃; for 12h; Autoclave; Overall yield = 82 %; General procedure for asymmetric hydrogenation General procedure: In a nitrogen-filled glovebox, a stainless steel autoclave was charged with [Ir(cod)Cl]2 (3.4 mg, 0.05 mmol) and (Sc,Rp,Sc)-L3 (6.1 mg, 0.11 mmol) in 1.0 mL of dry MeOH. After stirring for 1h at room temperature, a solution of the substrates 1 (1.0 mmol) and t-BuOK (5.6 mg, 0.05 mmol) in 2.0 mL of MeOH was added to the reaction mixture, and then the hydrogenation was performed at room temperature under an H2 pressure of 10 bar for 12 h. The solvent was then evaporated and the residue was purified by flash column chromatography to give the corresponding hydrogenation product, which was analyzed by chiral HPLC to determine the enantiomeric excesses.
With hydrogen; acetic acid In tetrahydrofuran at 59.84℃; for 3h; Autoclave; Optical yield = 86 %ee; enantioselective reaction; 2.3 Hydrogenation General procedure: To a 100mL autoclave, a singlesubstrate (MAA, AA, HB or 2O, 101mmol) for individualhydrogenation or a mixture of the substrate (AA, HB or 2O,50.5mmol) and MAA (50.5mmol) for competitive hydrogenationwas placed with acetic acid (0.2 mL) and TA-MRNi orMRNi (400 mg). Hydrogen was injected (10 MPa) and the autoclavewas heated to 333 K. Reciprocating shaking was appliedto initiate the catalytic reaction. The reaction time was limitedto 1 h with MRNi to obtain a low conversion of the substrate,while to 3h with TA-MRNi. The accuracy of the conversionwas estimated from reproducibility to be within 5% of theobserved one. The reaction mixture was separated from thecatalyst by decantation. NMR was used to determine the conversionof the substrate.Enantioselective hydrogenations of AA and HB were carriedout over TA-MRNi to confirm the reported enantioselectivityunder the previous reaction conditions, where the substrate(1.0 g), acetic acid (0.2 mL) and THF (10 mL) were used. Priorto determining enantioselectivity, the reaction products wereacetylated with acetic anhydride and pyridine. Enantiomericexcess of the products was determined with gas chromatography(Shimadzu GC-17A equipped with a CP-Chirasil DEXCBcapillary column). Enantiomeric excess (%ee) is defined as, %ee = 100 × ([R] - [S]/([R]+ [S] (1) where [R] and [S] denote the amounts of the (R)- and (S)-products.
86 % ee With dichloro(benzene)ruthenium(II) dimer; (M)-1,1'-bis[(R)-1-(tert-butyldiphenylsiloxy)prop-2-yl]-3,3'-bis(diphenylphosphanyl)-2,2'-biindolyl; hydrogen In ethanol at 22℃; for 24h; Autoclave; Overall yield = 73 %; enantioselective reaction;
82 % ee With dichloro(benzene)ruthenium(II) dimer; C78H78N2O2P2Si2; hydrogen In ethanol at 22℃; for 24h; Autoclave; Overall yield = 35 %;
With hydrogen In 1,4-dioxane Autoclave; Optical yield = 40 %ee;
60 % ee With hydrogen; acetic acid In tetrahydrofuran; water at 59.84℃; for 24h; Autoclave; enantioselective reaction; 2.3 Hydrogenation. To a 250mL glass autoclave (Parr,Hydrogenation Apparatus, Model 3916) equipped with a thermocouple,heating mantle, temperature controller, pressuregauge, gas cylinder and reciprocal shaker, MAA was placedwith THF (50 mL), acetic acid (0.2 mL) and TA-NaBr-MRNi(400 mg). The residual air in the reactor was replaced withhydrogen by performing a cycle of refill of H2 at 0.5 MPa/release at 0.1 MPa five times and then hydrogen was injectedinto the reactor for the reaction (total pressure, 0.130.50MPa).Hydrogen pressure was kept constant during the hydrogenationreactions by use of a hydrogen reservoir. The partial hydrogenpressure was calculated assuming a Raoult’s law for the solventTHF (ca. 0.08 MPa at 333 K). The autoclave was heated to333K and then reciprocating shaking was applied to initiate thecatalytic reaction. The reciprocating cycle was 175 cycles perminute. The reaction was conducted for 16 h, 24 h, 32 h, 48 h or96 h with TA-NaBr-MRNi. The reaction mixture was separatedfrom the catalyst by decantation. NMR was used to determinethe conversion of the substrate. Prior to determining enantioselectivity,the reaction products were acetylated with aceticanhydride and pyridine. Enantiomeric excess of the productswas determined with gas chromatography (Shimadzu GC 17Aequipped with a CP-Chirasil DEX-CB capillary column, 0.25mm 25m with a helium flow in 32cm/s) at 100 °C; Rt =5.18min for (S)- and 5.32min for (R)-product. Analyticalcondition at different temperature has been reported elsewhere.4Enantiomeric excess (%ee) is defined as,%ee 100 R S=R S 1where [R] and [S] denote the amounts of the (R)- and (S)-products.
4 % ee With hydrogen In methanol at 60℃; for 22h; enantioselective reaction;
24 % ee With hydrogen In methanol at 60℃; for 22h; enantioselective reaction;
With hydrogen In methanol; water at 60℃; for 1.5h; enantioselective hydrogenation, other acetoaceates;
With C32H39BrMnN2O2P; potassium <i>tert</i>-butylate; hydrogen In methanol at 20℃; for 16h; Glovebox; Autoclave; Optical yield = 30 percent ee; enantioselective reaction; 134 Example 134: Asymmetric hydrogenation of ketones catalyzed by Io General procedure: In a glove box, add manganese complex (R, R)-Io (3.3mg, 0.005mmol), potassium tert-butoxide (1.12mg, 0.01mmol), solvent, ketone substrate (0.5 mmol). After sealing the autoclave, take it out of the glove box and fill it with 30 bar hydrogen. The reaction kettle was stirred at room temperature for 16 hours. Slowly release excess hydrogen. The reaction solution was separated by column chromatography to obtain the separation yield. The ee value was determined by HPLC. The reaction results are listed in Table 4. Among them, the absolute configuration of the product is confirmed by the optical comparison with the standard product, where m alcohol is the mass (g) of the product separated by column chromatography, and n ketone is the molar amount of the ketone substrate ( mol), M alcohol is the molecular weight of the product (g/mol).
80.8 % ee With D-Glucose; cobalt(II); BaSDR1 reductase; NADH In aq. phosphate buffer at 35℃; Enzymatic reaction; enantioselective reaction;

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  • 20
  • [ 105-45-3 ]
  • [ 53562-86-0 ]
  • [ 3976-69-0 ]
  • [ 29267-46-7 ]
YieldReaction ConditionsOperation in experiment
1: 97% 2: 3% With hydrogen In methanol at 30℃; for 35h; other: catalysts, solvents, time, pressure, temperatures;
  • 21
  • [ 105-45-3 ]
  • [ 53562-86-0 ]
  • [ 29267-46-7 ]
YieldReaction ConditionsOperation in experiment
1: 3% 2: 97% With hydrogen In methanol at 30℃; for 35h;
1: 96% 2: 4% With hydrogen In methanol at 30℃; for 35h; in an autoclave; enantioselectivity; other catalysts;
1: 4% 2: 96% With hydrogen In methanol at 30℃; for 35h; in an autoclave;
  • 22
  • [ 142176-65-6 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
81% With nickel
  • 23
  • [ 53562-86-0 ]
  • [ 98-59-9 ]
  • [ 91366-13-1 ]
YieldReaction ConditionsOperation in experiment
70% In pyridine at -5 - 0℃; for 48h;
With pyridine Ambient temperature;
With pyridine; triethylamine In toluene at 0 - 20℃; Inert atmosphere; Methyl (R)-3-(tosyloxy)butanoate [(R)-1]. A solution of p-toluenesulfonyl chloride (35.1 g, 184 mmol,1.15 equiv) in toluene (50 mL) was added in a dropwise manner to a stirred solution of methyl(R)-3-hydroxybutanoate (20 g, 160 mmol) in anhydrous pyridine (50 mL) under N2. The reactionmixture was stirred overnight after warming to room temperature and quenched with 1N aqueousHCl (100 mL). The resulting mixture was then extracted with EtOAc (3 200 mL) and the combinedorganic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated invacuo. The crude residue was purified by SiO2 flash chromatography to give the title compound(R)-1 (38.7 g, 84%) as a white solid.
  • 24
  • [ 53562-86-0 ]
  • [ 74-88-4 ]
  • [ 66767-60-0 ]
  • methyl (2R,3S)-3-hydroxy-2-methylbutanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With lithium diisopropyl amide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane 1) -50 deg C to r. t., 2) reflux, 45 min; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With lithium diisopropyl amide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide at -50℃; Title compound not separated from byproducts;
  • 25
  • [ 14218-11-2 ]
  • [ 53562-86-0 ]
  • C39H36O12 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With silver trifluoromethanesulfonate; tetramethylurea In dichloromethane at 0℃; for 0.5h; Yield given;
  • 26
  • [ 114607-87-3 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
80%
  • 27
  • [ 53562-86-0 ]
  • [ 39637-99-5 ]
  • methyl (3S)-3-<(S)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl>butyrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With pyridine In tetrachloromethane for 12h; Ambient temperature;
  • 28
  • [ 53562-86-0 ]
  • [ 18162-48-6 ]
  • [ 148555-62-8 ]
YieldReaction ConditionsOperation in experiment
100% With 1H-imidazole; dmap In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere; Methyl (R)-3-tert-butyldimethylsilyloxybutyrate (S-10) Under an Ar atmosphere, TBSCl (1.78 g, 105 mmol) was added to a solution of (+)-(S)-Ethyl 3-hydroxybutylate (20) (11.8 g, 100 mmol), imidazole (10.2 g, 150 mmol) and DMAP (6.1 g, 50 mmol) in DMF (300 mL) at 0°C, and the mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with Et2O, successively washed with 10% HCl aq. and sat. NaHCO3 aq., dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by column chromatography on silica gel to afford the TBS ether (21) (23.3 g, 100 mmol, quant.) as a colorless oil.
99% With 1H-imidazole In N,N-dimethyl-formamide at 70℃; for 8h;
98% With 1H-imidazole In N,N-dimethyl-formamide at 20℃;
95% With dmap; triethylamine In dichloromethane at 20℃; for 13h;
95% With triethylamine In dichloromethane at 0 - 20℃; for 13h; 1 Process 1) Synthesis of (+)-methyl 3-(tert-butyldimethylsilyloxy) butyrate Process 1) Synthesis of (+)-methyl 3-(tert-butyldimethylsilyloxy) butyrate Tert-butyldimethylsilylchloride (1.8 g, 12 mmol) was added under an argon atmosphere at 0° C. to a dichloromethane (30 ml) solution of (+)-(S)-methyl 3-hydroxy-butyrate (1.18 g, 10 mmol), triethylamine (3 ml) and 4-dimethylaminopyridine (catalyst amount), and then stirred for 13 hours at room temperature. Following this, the reaction solution was diluted using dichloromethane. Then, the organic layer, which had been washed in succession with 10% hydrochloric acid, saturated sodium bicarbonate water, and saturated saline solution, was dried over magnesium sulfate, filtered, and the solvent thereof was distilled off. The resulting residue was then separated using silica-gel column chromatography (hexane:ethyl acetate=99:1). The subject compound was obtained as a colorless oily matter (2.2 g, 95%). 1H-NMR (300 MHz) (CDCl3) δ: 4.26 (1H, m, 3-H), 3.66 (3H, s, COOMe), 2.48 (1H, dd, J=7.7 Hz, 14 Hz, 2-H), 2.37 (1H, dd, J=5.2 Hz, 14 Hz, 2-H), 1.19 (3H, d, J=6.0 Hz, CH3), 0.86 (9H, s, t-Bu-Si), 0.06 (3H, s, Me2-Si), 0.04 (3H, s, Me2-Si) 13C-NMR (75 MHz) (CDCl3) δ: 172.03 (s), 66.02 (d), 51.59 (q), 44.94 (t), 25.96 (q), 18.19 (s), -4.22 (q), -4.78 (q) IR (neat): 1742 cm-1 (C=O) Mass spectrum: m/z 217 (M+-15), 175 (M+-57)
95.4% With 1H-imidazole In dichloromethane at 0 - 30℃; for 3h; Inert atmosphere; 8 Example 8: methyl (S)-3-((tert-butyldimethylsilyl)oxy)butanoate To a 500mL three-necked flask, methyl (S)-3-hydroxybutanoate (compound of formula Xb) (20g, 0.l7mol) and imidazole (23g, 0.34mo1) were added into anhydrous dichloromethane (350 mL). Nitrogen was used to replace the air in the flask three times.Tert-butyldimethylsilyl chloride (TBSC1, 30.5g, 0.2mol) was added slowly to this suspension at 0°C. After this addition, the reaction mixture was stirred for 3h at room temperature. TLC showed the completion of the reaction. Then the reaction mixture was poured into ice water (300mL) to quench. The organic layer was washed with water (three times) and brine (three times), dried over sodium sulfate, filtered and concentrated under reduced pressure to drynessto obtain the title compound. Yield 37.5g (95.4%).
94% With 1H-imidazole In dichloromethane at -5 - 20℃; for 3h; (R)-methyl 3-((tert-Butyldimethylsilyl)oxy)butanoate General procedure: To a suspension of (R)-methyl 3-hydroxybutanoate (2a) (20 g, 0.17 mol) and imidazole (23 g, 0.34 mol) in dichloromethane (DCM) (350 mL), TBSCl (30.5 g, 0.2 mol) was added at -5 to 0°C. After this addition, the reaction mixture was stirred for 3 h at room temperature. TLC showed the complete consumption of 2a. Then, ice water (300 mL) was added and the mixture was stirred for 5 min and then separated. The organic phase was washed with brine, dried over Na2SO4, and filtered and concentrated to obtain the crude product as colorless oil
88% With 1H-imidazole; dmap In N,N-dimethyl-formamide at 0℃;
85% With 1H-imidazole In dichloromethane for 14h; Ambient temperature;
81% With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 1h;
62% With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; 153.1 To a stirred mixture of methyl-(S)-3 -hydroxy butyrate (25 0 g, 211.6 mmol, 1.0 equiv) in DMF (250 0 mL) were added t-butyldimethylchlorosilane (38.3 g, 253.9 mmol, 1.2 equiv) and 111- imidazole (21.6 g, 317.4 mmol, 1.5 equiv) at 0 degrees C. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted w th EtOAc (3 x 500 mL). The combined organic layers wrere washed with brine (2x500 mL), dried over anhydrous MgS04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 : 1) to afford the desired compound methyl (3S)-3- [(tert-butyldimethylsilyl)oxy]butanoate (33 g, 62%) as colorless oil. LCMS (ES, m/z): 233 i M * 1 f]
With 1H-imidazole In N,N-dimethyl-formamide
With 1H-imidazole In dichloromethane at 20℃; for 3h;
With 1H-imidazole In dichloromethane at 20℃; for 6h;
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 19.5h;
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 3h; Cooling with ice; 2-20-1 (4R)-4-amino-2-methyl-5-(pyridin-2-yl)pentan-2-ol dihydrochloride To a solution of (S)-3-hydroxybutanoic acid methyl ester (2.000 g) in N,N-dimethylformamide (40 mL) was added imidazole (1.383 g) and tert-butyldimethylchlorosilane (3.062 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added ice, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to afford (3S)-3-(tert-butyldimethylsilyloxy)butanoic acid methyl ester (3.934 g).
With 1H-imidazole In ethyl acetate at 0 - 25℃; for 16h;
3.934 g With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 3h; Cooling with ice; 2-20-1 (4R) -4-amino-2-methyl-5- (pyridin-2-yl) pentan-2-ol dihydrochloride (S) -3-hydroxybutanoic acid methyl ester(2.000 g)Of N, N-dimethylformamide (40 mL)Imidazole (1.383 g) and tert-butyldimethylchlorosilane (3.062 g) were added to the solution under ice-cooling and the mixture was stirred at room temperature for 3 hours. Ice was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatographyThe residue was purified by matte chromatography (eluent: ethyl acetate / n-hexane)(3S) -3- (tert-butyldimethylsilyloxy) butanoic acid methyl ester (3.934 g).To a solution of the product (3.934 g) in diethyl ether (60 mL) was added diisobutylaluminum hydride n-hexane solution (1.02 mol / L, 22 mL) at -78 ° C. and the mixture was stirred at the same temperature for 2 hours. An aqueous potassium sodium tartrate solution was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. The crude product was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatographyThe residue was purified by matte chromatography (eluent: ethyl acetate / n-hexane)(3S) -3- (tert-butyldimethylsilyloxy) butanal (3.076 g).(R) - (+) - 2-methylpropane-2-sulfinamide (1.246 g) and tetraethyl orthotitanate (2.886 g) were added to a tetrahydrofuran (20 mL) solution of the product (1.600 g)And the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, diluted with ethyl acetate, and passed through a celite pad. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane)(R) -N - [(1 E, 3 S) -3- (tert-butyldimethylsilyloxy) butylidene] -2-methylpropane-2-sulfinamide(2.050 g).An n-butyllithium n-hexane solution (2.6 mol / L, 2.2 mL) was added at -78 ° C. to a tetrahydrofuran (3 mL) solution of 2-methylpyridine (0.572 g), and the mixture was stirred at the same temperature for 30 minutes . A solution of tetrahydrofuran (3 mL) of (R) -N - [(1E, 3S) -3- (tert-butyldimethylsilyloxy) butyridene] -2-methylpropane-2-sulfinamide (1.250 g) And the mixture was further stirred for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane)(R) -N - [(2R, 4S) -4- (tert-butyldimethylsilyloxy) -1- (pyridin-2- yl) pentane-2-yl] -2-methylpropane-2-sulfinamide(0.639 g) as a highly polar diastereomer.Tetrahydrofuran (6 mL) of the product (0.400 g)Tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 2 mL) was added to the solution under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate)(R) -N - [(2R, 4S) -4-hydroxy-l- (pyridin-2- yl) pentan- 2-yl] -2- methylpropane-2-sulfinamide (0.284 g) .Dess-Martin periodinane (0.509 g) was added to a solution of the product (0.284 g) in dichloromethane (10 mL) under ice cooling, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous solution of sodium sulfite and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silicaPurification by gel column chromatography (eluent: methanol / ethyl acetate)(R) -2-methyl-N - [(2R) -4-oxo-1- (pyridin-2-yl) pentan-2-yl] propane-2-sulfinamide (0.201 g).Methyl magnesium bromide diethyl ether solution (3.0 mol / L, 0.91 mL) was added to a tetrahydrofuran (3 mL) solution of the product (0.201 g) under ice cooling, and the mixture was stirred at the same temperature for 7 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressureThe obtained residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate)(0.015 g) of (R) - N - [(2R) -4-hydroxy-4-methyl- 1 - (pyridin- 2-yl) pentan-2-yl] Obtained. To a solution of the product (0.015 g) in 1,4-dioxane (0.5 mL) was added hydrogen chloride 1, 4-dioxane solution (4 mol / L, 0.5 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with n-hexane to give the title compound (0.015 g). Structural formula, spectral data and purification conditions are shown in Table 33.
Stage #1: (S)-3-hydroxybutyric acid methyl ester; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Stage #2: With water In N,N-dimethyl-formamide 17.9 To a solution of methyl-(S)-3-hydroxybutyrate (15 g, 127 mmol) in anhydrous DMF (100 mL) under N2 is added tert-butyldimethylsilyl chloride (21.1 g, 140 mmol), followed by imidazole (9.52 g, 140 mmol). The reaction mixture is stirred at room temperature overnight. The reaction is quenched with water (100 mL), and extracted with hexane. The organic phase is washed with water and brine, dried over Na2SO4. Removal of the solvent under reduced pressure affords a colorless oil which is dissolved in anhydrous THF (100 mL) and cooled to -78° C. DIBAL (381 mL, 1M in THF) is added slowly, and the reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is cooled to 0° C., quenched with saturated sodium tartrate carefully, and then extracted with EtOAc (3×). The organic layers are combined, washed with brine, and dried over Na2SO4. Removal of the solvent under reduced pressure affords a colorless oil, which is dissolved in anhydrous CH2Cl2 (80 mL). TsCl (18.2, 95.6 mmol) is added in one portion, the mixture is cooled to 0° C., and pyridine (15.5 mL, 191.2 mmol) is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction is quenched with aqueous HCl (1N, 150 mL), and extracted with CH2Cl2. The organic phase is washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is treated with 30 g of ammonium carbonate resin in CH2Cl2 (200 mL) and MeOH (70 mL) at room temperature. After stirring for 3 h, the resin is removed via filtration through celite, the filtrate is concentrated under reduced pressure, and the residue is purified by flash chromatography on silica gel (hexane/EtOAc: 8/1) to afford the title compound as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ: 7.78 (d, 2H), 7.33 (d, 2H), 4.10 (m, 2H), 3.89 (m, 1H), 2.44 (s, 3H), 1.68-1.77 (m, 2H), 1.09 (d, 3H), 0.80 (s, 9H), 0.01 (s, 3H), -0.03 (s, 3H). LC-MS m/z (M+Na): 381.

Reference: [1]Sugimoto, Kenji; Kobayashi, Yuta; Hori, Ayana; Kondo, Takashi; Toyooka, Naoki; Nemoto, Hideo; Matsuya, Yuji [Tetrahedron, 2011, vol. 67, # 40, p. 7681 - 7685]
[2]Jiao Ying; Yoshihara; Ichihara [Bioscience, Biotechnology and Biochemistry, 1995, vol. 59, # 6, p. 1032 - 1035]
[3]Kobayashi; Kumar; Kurachi; Acharya; Yamazaki; Kitazume [Journal of Organic Chemistry, 2001, vol. 66, # 6, p. 2011 - 2018]
[4]Matsuya, Yuji; Kawaguchi, Takanori; Nemoto, Hideo; Nozaki, Hiroshi; Hamada, Hiroki [Heterocycles, 2003, vol. 59, # 2, p. 481 - 484] Ishihara, Kentaro; Kawaguchi, Takanori; Matsuya, Yuji; Sakurai, Hiroaki; Saiki, Ikuo; Nemoto, Hideo [European Journal of Organic Chemistry, 2004, # 19, p. 3973 - 3978]
[5]Current Patent Assignee: LEAD CHEM; LEAD CHEMICAL CO.,LTD. - US2006/30720, 2006, A1 Location in patent: Page/Page column 4
[6]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - WO2018/108130, 2018, A1 Location in patent: Page/Page column 20; 24
[7]Pan, Tingting; Xia, Chunguang; Jiang, Huijuan; Zhang, Zhongtang; Zhu, Xueyan; Yang, Yulei [Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 6, p. 582 - 585]
[8]Yue, Qiming; Zhao, Yi; Sun, Baohou; Hai, Li; Guo, Li; Wu, Yong [Chinese Journal of Chemistry, 2015, vol. 33, # 10, p. 1145 - 1152]
[9]Ishiyama, Haruaki; Ishibashi, Masami; Ogawa, Akio; Yoshida, Shonen; Kobayashi, Jun'ichi [Journal of Organic Chemistry, 1997, vol. 62, # 12, p. 3831 - 3836]
[10]Ono, Machiko; Nakamura, Hiroshi; Konno, Fumi; Akita, Hiroyuki [Tetrahedron Asymmetry, 2000, vol. 11, # 13, p. 2753 - 2764]
[11]Current Patent Assignee: COMET THERAPEUTICS - WO2020/113209, 2020, A1 Location in patent: Paragraph 2121
[12]Kobayashi, Yuichi; Kumar, Biju G.; Kurachi, Tomoaki [Tetrahedron Letters, 2000, vol. 41, # 10, p. 1559 - 1563]
[13]Kusaka, Shin-Ichi; Dohi, Suguru; Doi, Takayuki; Takahashi, Takashi [Tetrahedron Letters, 2003, vol. 44, # 49, p. 8857 - 8859]
[14]Takahashi, Takashi; Kusaka, Shin-Ichi; Doi, Takayuki; Sunazuka, Toshiaki; Omura, Satoshi [Angewandte Chemie - International Edition, 2003, vol. 42, # 42, p. 5230 - 5234]
[15]Location in patent: experimental part Toriizuka, Yosuke; Kinoshita, Eri; Kogure, Noriyuki; Kitajima, Mariko; Ishiyama, Aki; Otoguro, Kazuhiko; Yamada, Haruki; Omura, Satoshi; Takayama, Hiromitsu [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 24, p. 10182 - 10189]
[16]Current Patent Assignee: KISSEI PHARMACEUTICAL COMPANY LIMITED - EP3315492, 2018, A1 Location in patent: Paragraph 0215
[17]Yu, Wensheng; Tong, Ling; Selyutin, Oleg; Chen, Lei; Hu, Bin; Zhong, Bin; Hao, Jinglai; Ji, Tao; Zan, Shuai; Yin, Jingjun; Ruck, Rebecca T.; Curry, Stephanie; McMonagle, Patricia; Agrawal, Sony; Rokosz, Laura; Carr, Donna; Ingravallo, Paul; Bystol, Karin; Lahser, Frederick; Liu, Rong; Chen, Shiying; Feng, Kung-I; Cartwright, Mark; Asante-Appiah, Ernest; Kozlowski, Joseph A. [Journal of Medicinal Chemistry, 2018, vol. 61, # 9, p. 3984 - 4003]
[18]Current Patent Assignee: KISSEI PHARMACEUTICAL COMPANY LIMITED - JP2018/108988, 2018, A Location in patent: Paragraph 0232
[19]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - US2006/9456, 2006, A1 Location in patent: Page/Page column 54
  • 29
  • [ 53562-86-0 ]
  • [ 81927-55-1 ]
  • [ 90124-15-5 ]
YieldReaction ConditionsOperation in experiment
89% With trifluorormethanesulfonic acid In dichloromethane at 20℃; for 24h;
With trifluorormethanesulfonic acid In hexane; dichloromethane at 0℃;
With trifluorormethanesulfonic acid In hexane; dichloromethane for 4h; Ambient temperature;
With cyclohexane In dichloromethane; trifluorormethanesulfonic acid

  • 30
  • [ 53562-86-0 ]
  • [ 58479-61-1 ]
  • [ 215444-96-5 ]
YieldReaction ConditionsOperation in experiment
100% With 1H-imidazole In N,N-dimethyl-formamide
100% With 1H-imidazole In N,N-dimethyl-formamide at 53℃; for 18h;
99% With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃;
95% Stage #1: (S)-3-hydroxybutyric acid methyl ester With 1H-imidazole In dichloromethane at 0℃; Stage #2: tert-butylchlorodiphenylsilane In dichloromethane at 25℃; Further stages.;
92.4% With 1H-imidazole In dichloromethane at 20℃; for 4.5h; 31a methyl (S)-(+)-3-hydroxybutyrate (0.48 g, 4.04 mmol) (Aldrich) was dissolved in dichloromethane (6 ML, dried over molecular sieves).imidazole (0.39 g, 5.65 mmol) (Aldrich) was added.When all had dissolved, tert-butyldiphenylsilyl chloride (1.05 ML, 4.04 mmol) was added dropwise and the mixture was stirred at room temperature for 4.5 hours.The reaction mixture was diluted with additional dichloromethane, washed with water (2x) and brine, dried over anhydrous sodium sulfate, filtered and concentrated.Purification by flash chromatography (Biotage 40M, 5:95 ethyl acetate-hexanes) gave (S)-3-(tert-butyl-diphenyl-silanyloxy)-butyric acid methyl ester. (Yield 1.33 g, 92.4%).
64% With 1H-imidazole In N,N-dimethyl-formamide at 20℃; Cooling with ice; 1 tert-Butyl(chloro)diphenylsilane (15.282 g, 55.6 mmol) was added dropwise to an ice- cooled and stirred solution of (S)-3 -hydro xybutanoic acid methyl ester (5.473 g, 46.3 mmol) and iH-imidazole (6.939 g, 102 mmol) and DMAP (0.566 g, 4.63 mmol) in DMF (250 mL). After 10 min., the cloudy reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was taken up in EtOAc, then washed successively with H2O (3 x), IN HCl and a sat. NaHCO3 solution. The organic phase was dried (Na2SO4), filtered and concentrated to give a viscous colourless oil. Yield: 10.614 g of intermediate Dl (64 %).
With 1H-imidazole In dichloromethane at 0 - 20℃; for 3h; 15 4.15. (S)-3-((tert-Butyldiphenylsilyl)oxy)butan-1-ol (25) To a solution of 8 (2.36 g, 20 mmol) in DCM (20 mL), imidazole (1.64 g, 24 mmol) and TBDPSCl (6.55 g, 24 mmol) were added at 0 °C. Then the mixture was allowed to room temperature and stirred for 3 h, after which time the reaction was quenched by adding H2O and diluted with ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3*100 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated and flash column chromatography gel (petroleum ether-EtOAc, 6:1) to obtained (S)-methyl 3-((tert-butyldiphenylsilyl)oxy)butanoate as yellow oil. Rf=0.8 (petroleum ether-EtOAc, 9:1); [α]D20 +4.1 (c=1.0, CHCl3). IR (KBr) νmax=3071, 2959, 2932, 2858, 1740, 1430, 1378, 1298, 1194, 1083, 998, 822, 739, 705, 611, 509 cm-1. 1H NMR (300 MHz, CDCl3): 7.72 (t, J=7.1 Hz, 4H), 7.47-7.37 (m, 6H), 4.39-4.32 (m, 1H), 3.61 (s, 3H), 2.60 (dd, J=14.1, 7.1 Hz, 1H), 2.43 (dd, J=14.1, 6.0 Hz, 1H), 1.15 (d, J=6.0 Hz, 3H), 1.07 (s, 9H). 13C NMR (75 MHz, CDCl3): 171.7, 135.7, 134.1, 133.7, 129.5, 127.4, 66.8, 51.2, 44.3, 26.8, 23.5, 19.0; MS (ESI): m/z=379 [M+Na]+. HRMS: calcd for C21H28O3SiNa [M+Na]+: 379.1699: found: 379.1697.

  • 31
  • [ 53562-86-0 ]
  • [ 124-63-0 ]
  • (S)-3-Methanesulfonyloxy-butyric acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With triethylamine In dichloromethane at 0℃;
91% With triethylamine In dichloromethane for 1h; Ambient temperature;
  • 32
  • [ 53562-86-0 ]
  • 4-vinyloxyazetidin-2-one [ No CAS ]
  • (4S,6R)-4-Methyl-5-oxa-1-aza-bicyclo[4.2.0]octan-8-one [ No CAS ]
  • (4S,6S)-4-Methyl-5-oxa-1-aza-bicyclo[4.2.0]octan-8-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multistep reaction. Title compound not separated from byproducts;
  • 34
  • [ 110-87-2 ]
  • [ 53562-86-0 ]
  • (S)-3-(Tetrahydro-pyran-2-yloxy)-butyric acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% With hydrogen cation
  • 35
  • [ 1487-49-6 ]
  • [ 53562-86-0 ]
  • [ 3976-69-0 ]
YieldReaction ConditionsOperation in experiment
With air; cells of Geotrichum candidum IFO5767 In water at 30℃; for 24h;
With pentyl cage-coated capillary column Resolution of racemate;
With homochiral metal-organic cage [Zn3(deprotonated [3+3] macrocyclic Schiff base of trans-1,2-diaminocyclohexane and 4-tert-butyl-2,6-diformylphenol)2] coated capillary column In dichloromethane at 112℃; Resolution of racemate; enantioselective reaction;
  • 36
  • [ 53562-86-0 ]
  • [ 294198-49-5 ]
  • [ 473555-54-3 ]
YieldReaction ConditionsOperation in experiment
75% With dmap; (1S)-10-camphorsulfonic acid; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 48h;
  • 37
  • [ 53562-86-0 ]
  • [ 89238-99-3 ]
  • [ 350848-03-2 ]
YieldReaction ConditionsOperation in experiment
95% With 10-camphorsulfonic acid In dichloromethane at 20℃; for 7h;
70% With D,L-camphorsulfonic acid In dichloromethane at 20℃; for 12h; Inert atmosphere;
With camphor-10-sulfonic acid In dichloromethane
  • 39
  • [ 53562-86-0 ]
  • [ 74-88-4 ]
  • [ 66767-60-0 ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: (S)-3-hydroxybutyric acid methyl ester With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: methyl iodide at -78℃; for 1.5h;
78% With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; lithium diisopropyl amide In tetrahydrofuran at -78℃;
77% Stage #1: (S)-3-hydroxybutyric acid methyl ester With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran; hexane at -78℃; for 1.5h; Inert atmosphere;
Stage #1: (S)-3-hydroxybutyric acid methyl ester With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.333333h; Stage #2: methyl iodide In tetrahydrofuran at -78 - 20℃; for 2.25h; To a stirring solution of diisopropylamine (2 eq. , 366 mmol, 51.3 mL) in dry THF (200 mL) at-78°C was added slowly a 1.6 M solution of n-BuLi (2 eq., 366 mmol, 230 mL) over a period of 20 min. The reaction mixture was warmed to 0°C and allowed to stir for 45 min after which the solution was cooled back to-78°C. Then, a solution of methyl-3-hydroxybutyrate (21.6 g, 183 mmol) in dry THF (100 mL) was added slowly over a period of 20 min after which neat MeI (5eq, 915 mmol, 57 mL) was added over a period of 5 min. The reaction mixture was allowed to stir for 10 min at-78°C then warmed to rt, and stirred for 2h. The reaction was quenched with a saturated solution of NH4Cl (350 mL), extracted with Et20 (3 x 400 mL), the combined organic extracts were washed with a saturated solution of NH4CI (350 mL), water (2 x 450 mL), brine (450mL), dried with K2CO3, filtered and concentrated. The crude alcohol 555-RB-224 was dissolved in dry DMF (100 mL), imidazole (2. 5eq, 363 mmol, 24.7 g) was added and the mixture was cooled to 0°C in ice/water bath. Then TBSCI (1. 2eq, 33.0 mmol, 5 g) was added, the mixture was allowed to warm slowly to rt and stirred for 16h after which a saturated solution of NaHC03 (250 mL) was added. The mixture was extracted with Et20 (3 x 250 mL) and the combined organic extracts were washed with a saturated solution of NaHC03 (350 mL), water (3 x 350 mL), brine (350 mL), dried with Na2S04, filtered and concentrated. The crude product was purified by chromatography on silica gel using 5% EtOAc/hexane to give 31.7 g (129 mmol, 70% 2 steps) of the protected compound 554-RB-225
Stage #1: (S)-3-hydroxybutyric acid methyl ester With lithium diisopropyl amide In tetrahydrofuran Stage #2: methyl iodide
Stage #1: (S)-3-hydroxybutyric acid methyl ester With lithium diisopropyl amide In tetrahydrofuran at -78 - 20℃; for 0.333333h; Inert atmosphere; Schlenk technique; Stage #2: methyl iodide In tetrahydrofuran at -78 - 0℃; for 3h; Inert atmosphere; Schlenk technique;

  • 40
  • [ 53562-86-0 ]
  • [ 6638-79-5 ]
  • [ 474825-97-3 ]
YieldReaction ConditionsOperation in experiment
89% With isopropylmagnesium chloride In tetrahydrofuran at -30 - 0℃; for 3.5h;
  • 41
  • [ 73881-10-4 ]
  • [ 53562-86-0 ]
  • 2-(1-hydroxy-ethyl)-oct-4-enoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-3-hydroxybutyric acid methyl ester With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; lithium hexamethyldisilazane In tetrahydrofuran at -60℃; Stage #2: (E)-1-bromo-2-hexene In tetrahydrofuran at 0℃;
  • 42
  • [ 933786-60-8 ]
  • [ 53562-86-0 ]
  • (-)-(1'S,4E)-13-benzyloxy-2-(1'-hydroxy-ethyl)-tridec-4-enoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-3-hydroxybutyric acid methyl ester With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; lithium hexamethyldisilazane In tetrahydrofuran at -60℃; for 0.5h; Stage #2: (2E)-11-benzyloxy-1-bromo-undec-2-en In tetrahydrofuran at 0℃; for 4h;
  • 43
  • [ 53562-86-0 ]
  • [ 35329-44-3 ]
  • 2-(1-hydroxy-ethyl)-tridec-4-enoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-3-hydroxybutyric acid methyl ester With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; lithium hexamethyldisilazane In tetrahydrofuran at -60℃; Stage #2: (E)-Undec-2-enyl bromide In tetrahydrofuran at 0℃;
  • 44
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 16088-62-3 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
88% at 20℃; for 24h;
  • 45
  • [ 53562-86-0 ]
  • [ 914461-71-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / LDA; DMPU / tetrahydrofuran / -78 °C 2: 28 percent / triphenylphosphine; diethyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C
  • 46
  • [ 53562-86-0 ]
  • [ 459809-73-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 75 percent / DCC; DMAP; (+)-CSA / CH2Cl2 / 48 h / 20 °C 2: 86 percent / aq. AcOH / tetrahydrofuran / 12 h / 80 °C
  • 47
  • [ 53562-86-0 ]
  • [ 473555-56-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 75 percent / DCC; DMAP; (+)-CSA / CH2Cl2 / 48 h / 20 °C 2: 86 percent / aq. AcOH / tetrahydrofuran / 12 h / 80 °C 3: 69 percent / DCC; DMAP; (+)-CSA / CH2Cl2 / 48 h / 20 °C
  • 48
  • [ 114607-75-9 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: Candida guilliermondii 2: 80 percent / Raney nickel
  • 49
  • [ 53562-86-0 ]
  • [ 3461-39-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 87 percent / pyridine / CH2Cl2 / 2 h / 40 °C 2: 64 percent / CF3SO3H / 10 h / 80 °C
  • 50
  • [ 53562-86-0 ]
  • [ 99342-22-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: iPr2NLi / tetrahydrofuran; hexamethylphosphoric acid triamide; hexane / 1) -50 deg C to r. t., 2) reflux, 45 min 2: N,N-diethylaniline / CH2Cl2 / 144 h / Ambient temperature
Multi-step reaction with 2 steps 1: iPr2NLi / tetrahydrofuran; hexamethylphosphoric acid triamide; hexane / 1) -50 deg C to r. t., 2) reflux, 45 min 2: N,N-diethylaniline / CH2Cl2 / Ambient temperature
  • 51
  • [ 53562-86-0 ]
  • [ 99342-23-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: iPr2NLi / tetrahydrofuran; hexamethylphosphoric acid triamide; hexane / 1) -50 deg C to r. t., 2) reflux, 45 min 2: N,N-diethylaniline / CH2Cl2 / 144 h / Ambient temperature
Multi-step reaction with 2 steps 1: iPr2NLi / tetrahydrofuran; hexamethylphosphoric acid triamide; hexane / 1) -50 deg C to r. t., 2) reflux, 45 min 2: N,N-diethylaniline / CH2Cl2 / Ambient temperature
  • 52
  • [ 53562-86-0 ]
  • [ 99328-37-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: iPr2NLi / tetrahydrofuran; hexamethylphosphoric acid triamide; hexane / 1) -50 deg C to r. t., 2) reflux, 45 min 2: imidazole / dimethylformamide / 24 h / Ambient temperature
Multi-step reaction with 2 steps 1: iPr2NLi / tetrahydrofuran; hexamethylphosphoric acid triamide; hexane / 1) -50 deg C to r. t., 2) reflux, 45 min 2: imidazole / dimethylformamide / Ambient temperature
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 1.2: 1.5 h / -78 °C / Inert atmosphere 2.1: 1H-imidazole / dichloromethane / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 0.33 h / -78 - 20 °C / Inert atmosphere; Schlenk technique 1.2: 3 h / -78 - 0 °C / Inert atmosphere; Schlenk technique 2.1: pyridine / dichloromethane / 1 h / 0 - 20 °C / Inert atmosphere; Schlenk technique

  • 53
  • [ 53562-86-0 ]
  • [ 99328-40-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: iPr2NLi / tetrahydrofuran; hexamethylphosphoric acid triamide; hexane / 1) -50 deg C to r. t., 2) reflux, 45 min 2: imidazole / dimethylformamide / 24 h / Ambient temperature
Multi-step reaction with 2 steps 1: iPr2NLi / tetrahydrofuran; hexamethylphosphoric acid triamide; hexane / 1) -50 deg C to r. t., 2) reflux, 45 min 2: imidazole / dimethylformamide / Ambient temperature
  • 54
  • [ 106353-39-3 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 60 percent / ZnCl2, HAl(iBu)2 / tetrahydrofuran / -78 °C 2: 81 percent / Raney Nickel
  • 55
  • [ 105-45-3 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1) LiN(iPr)2 / 1) THF, 0 deg C, 2) THF, -78 deg C, 1 h 2: 60 percent / ZnCl2, HAl(iBu)2 / tetrahydrofuran / -78 °C 3: 81 percent / Raney Nickel
  • 56
  • [ 53562-86-0 ]
  • (S)-3-Amino-5-(tert-butyl-diphenyl-silanyloxy)-2-((S)-1-hydroxy-ethyl)-pentanoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: LDA / tetrahydrofuran / 2 h / -70 gradC to 0 gradC 2: TFA / 0.5 h / 0 °C
  • 57
  • [ 53562-86-0 ]
  • [ 1493-13-6 ]
  • [ 81927-55-1 ]
  • [ 182970-04-3 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; cyclohexane 3 Preparation of α-Hydroxyalkanoyl Alkanoate Methyl (S)-(+)-3-hydroxybutyrate (17) (2.223 g, 18.82 mmol) and benzyl 2,2,2-trichloroacetimidate (4.2 mL) were dissolved into 37.5 mL of cyclohexane/methylene chloride (2:1). After the addition of 0.2 mL of trifluoromethane sulfonic acid the reaction was stirred under nitrogen for one hour. The reaction was diluted with 75 mL of cyclohexane/methylene chloride (2:1) and filtered. The organic layer was washed with 50 mL of saturated sodium bicarbonate and 50 mL of distilled water. After drying with anhydrous sodium sulfate the solution was filtered and the solvents were removed on a rotovap. The resulting solid was purified using silica gel and elution with ether/hexane (1:4). Synthesis of (S)-3-benzyloxybutyric acid (19):
  • 58
  • [ 108-48-5 ]
  • methyl (S)-3-t-butyldimethylsilyloxybutanoate [ No CAS ]
  • aq. potassium sodium tartrate [ No CAS ]
  • [ 53562-86-0 ]
  • [ 75-09-2 ]
  • [ 69739-34-0 ]
  • (S)-3-t-butyldimethylsilyloxybutanal [ No CAS ]
YieldReaction ConditionsOperation in experiment
170 mg (98%) With diisobutylaluminium hydride In methanol; hexane; ethyl acetate; toluene 1 Preparation of (S)-3-t-Butyldimethylsilyloxybutanal STR12 EXAMPLE 1 Preparation of (S)-3-t-Butyldimethylsilyloxybutanal STR12 To a 500 ml round bottom flask was introduced 2.54 g (21.5 mmol) of methyl (S)-3-hydroxybutanoate (Aldrich Chemicals), to which was added 70 ml CH2 Cl2, and 5 ml of 2,6-lutidine. The reaction was stirred in an ice bath, and 4.94 ml (5.68 g, 21.5 mmol) of t-butyldimethylsilyl triflate was added dropwise. After stirring for 1 hour, the reaction was diluted with 250 ml of CH2 Cl2 and extracted three times with 50 ml of water. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using 10% ethyl acetate in hexane. This afforded 4.3 g (86%) of the product, methyl (S)-3-t-butyldimethylsilyloxybutanoate. To a 50 ml round bottom flask was introduced 200 mg (0.86 mmol) of methyl (S)-3-t-butyldimethylsilyloxybutanoate, to which was added 2.5 ml dry CH2 Cl2. The reaction was stirred in a dry ice/acetone bath, and 1.72 ml (2 eq.) of 1M diisobutylaluminum hydride in toluene was added dropwise. After stirring for 1 hour at -78° C., the reaction was quenched with 2 ml of MeOH and warmed to room temperature. The reaction was diluted with 25 ml of CH2 Cl2 and 8 ml saturated aq. potassium sodium tartrate was added. The organic layer was separated and dried over MgSO4 and the solvent was removed under reduced pressure. Thin layer chromatography using 10% ethyl acetate in hexane showed complete and clean conversion to a lower Rf spot. This afforded 170 mg (98%) of the product, (S)-3-t-butyldimethylsilyloxybutanal, which was used without purification to avoid racemization.
  • 59
  • nBu4 N+ [ No CAS ]
  • [ 53562-86-0 ]
  • [ 75-09-2 ]
  • methyl (S)-3-azidobutanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; triethylamine In methanesulfonyl chloride; benzene 29 Preparation of Methyl (S)-3-Azidobutanoate Preparation of Methyl (S)-3-Azidobutanoate To methyl (S)-3-hydroxybutanoate (1 mmol) is added 25 ml dry CH2 Cl2 and 1.5 ml of triethylamine. This mixture is stirred in an ice bath and 1.4 eq. of methanesulfonyl chloride is added dropwise. The reaction is stirred for 1 hour at 0° C., after which time the reaction is diluted with 300 ml of CH2 Cl2 and extracted twice with 50 ml of water, twice with 50 ml of 0.1N HCl twice with 50 ml aq. sat. NaHCO3 and once with 50 ml of brine. The organic layer is dried over magnesium sulfate and the solvent is removed under vacuum. To the crude residue is added 6 ml of benzene and 2.2 eq. of nBu4 N+ N3-. The reaction is heated at 65° C. for 18 hours, after which time the reaction is diluted with 300 ml of CH2 Cl2 and extracted twice with 50 ml of water and once with 50 ml of brine. The organic layer is dried over MgSO4 and the solvent is removed under vacuum. The residue is chromatographed on silica, affording methyl (S)-3-azidobutanoate.
  • 60
  • [ 53562-86-0 ]
  • [ 142569-60-6 ]
YieldReaction ConditionsOperation in experiment
128 Methyl 3(R)-acetylthiobutanoate Methyl 3(R)-acetylthiobutanoate The title compound was prepared from methyl 3(S)-hydroxybutyrate in a manner identical to the one described for the (S)-isomer in Example 127. [α]D25 =+20.7° (c=3, CHCl3)
128 Methyl 3(R)-acetylthiobutanoate Methyl 3(R)-acetylthiobutanoate The title compound was prepared from methyl 3(S)-hydroxybutyrate in a manner identical to the one described for the (S)-isomer in Example 127. [α]D25 =+20.7° (c=3, CHCl3)
  • 61
  • [ 53562-86-0 ]
  • [ 119687-47-7 ]
YieldReaction ConditionsOperation in experiment
2.b EXAMPLE 2 b) (S)-2-hydroxy-3-methoxycarbonyl-2-penten-4-olide, [α]D20 =-30° (3% in CHCl3), m.p. 94°-96° C., from (S)-3-hydroxybutyric acid methyl ester.
  • 62
  • [ 67-56-1 ]
  • [ 1033766-70-9 ]
  • [ 53562-86-0 ]
  • polygalacic acid 28-O-α-L-rhamnopyranosyl(1->3)-β-D-xylopyranosyl(1->4)-α-L-rhamnopyranosyl(1->2)-β-D-fucopyranoside [ No CAS ]
YieldReaction ConditionsOperation in experiment
88.4% With sodium methylate at 20℃; for 3h;
  • 63
  • [ 67-56-1 ]
  • [ 1033766-71-0 ]
  • [ 53562-86-0 ]
  • besysaponin C12 [ No CAS ]
YieldReaction ConditionsOperation in experiment
88.5% With sodium methylate at 20℃; for 3h;
  • 64
  • [ 67-56-1 ]
  • [ 1033766-72-1 ]
  • [ 53562-86-0 ]
  • [ 121340-61-2 ]
YieldReaction ConditionsOperation in experiment
88.4% With sodium methylate at 20℃; for 3h;
  • 65
  • [ 67-56-1 ]
  • [ 1033766-73-2 ]
  • [ 53562-86-0 ]
  • [ 121340-61-2 ]
YieldReaction ConditionsOperation in experiment
92.3% With sodium methylate at 20℃; for 3h;
  • 66
  • [ 67-56-1 ]
  • [ 1033766-74-3 ]
  • [ 53562-86-0 ]
  • [ 121340-61-2 ]
YieldReaction ConditionsOperation in experiment
88.8% With sodium methylate at 20℃; for 3h;
  • 67
  • [ 53562-86-0 ]
  • [ 83559-39-1 ]
  • [ 1192264-09-7 ]
YieldReaction ConditionsOperation in experiment
In toluene at 75℃; for 1.5h; Inert atmosphere;
  • 68
  • [ 1201813-85-5 ]
  • [ 53562-86-0 ]
  • [ 3976-69-0 ]
YieldReaction ConditionsOperation in experiment
With sodium perborate monohydrate In tetrahydrofuran; methanol; water at 20℃; for 12h; Inert atmosphere;
With sodium perborate In tetrahydrofuran; water at 20℃; Inert atmosphere;
  • 69
  • [ 53562-86-0 ]
  • [ 2816-24-2 ]
  • [ 1203719-12-3 ]
YieldReaction ConditionsOperation in experiment
4.8 mg With β-glucosidase In acetone at 20℃; for 1h; aq. acetate buffer;
  • 70
  • [ 53562-86-0 ]
  • [ 506-59-2 ]
  • [ 89209-12-1 ]
YieldReaction ConditionsOperation in experiment
63.5% Stage #1: N,N-dimethylammonium chloride With sodium methylate In methanol at 4 - 12.8℃; Large scale reaction; Stage #2: (S)-3-hydroxybutyric acid methyl ester In methanol at 2 - 4℃; Large scale reaction; Stage #3: With sulfuric acid In methanol; water at 0 - 14℃; Large scale reaction;
  • 71
  • [ 53562-86-0 ]
  • [ 879-18-5 ]
  • 1-(methoxycarbonyl)propan-2-yl 1-naphthoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine In dichloromethane
  • 72
  • [ 186581-53-3 ]
  • [ 300-85-6 ]
  • [ 53562-86-0 ]
  • [ 3976-69-0 ]
  • 73
  • methyl crotonate [ No CAS ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: bis[2-(diphenylphosphino)phenyl] ether; copper(l) chloride; sodium t-butanolate / tetrahydrofuran; methanol 2: Candida antarctica lipase immobilized on acrylic resin / hexane / 24 h / 70 °C / Sealed tube; Enzymatic reaction 3: sodium perborate tetrahydrate / tetrahydrofuran; water / 1 h / 20 °C
  • 74
  • [ 1185248-82-1 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
With sodium perborate tetrahydrate In tetrahydrofuran; water at 20℃; for 1h; 4.3 General procedure for oxidation and acetylation of β-borylated esters 2a-f General procedure: To a 25 mL round-bottomed flask was added the appropriate β-borylated ester (0.5 mmol), THF (2.5 mL), water (2.5 mL), and NaBO3·4H2O (2.5 mmol, 0.385 g). The reaction mixture was stirred for 1 h at room temperature and then extracted with ethyl acetate (2 × 5 mL). The organic phase was rinsed with a saturated aqueous solution of NaCl (10 mL) and dried over anhydrous MgSO4. After solvent evaporation, the crude mixture was treated with pyridine (1 mL) and Ac2O (0.7 mL) and stirred for 12 h at room temperature. The reaction was extracted with ethyl acetate (10 mL) and the organic phase was treated with a saturated aqueous solution of CuSO4 (2 × 10 mL), a saturated aqueous solution of NaCl (2 × 10 mL), and dried over anhydrous MgSO4.
  • 75
  • [ 67-56-1 ]
  • [ 1558036-26-2 ]
  • [ 124-41-4 ]
  • [ 53562-86-0 ]
YieldReaction ConditionsOperation in experiment
at 20℃; 4.6 Chiral investigation of the C1″-C4″ moiety of 3 A solution of 3 (0.5mg) in MeOH was stirred with NaOMe (0.2mg) at room temperature. After consumption of the starting 3 based on TLC analysis, acetic acid (1.0μL) was added to neutralize the solution. The mixture was sampled (0.1mL) and diluted with MeOH, which was subjected to gas chromatography equipped with Rt-γDEXsa (RESTEC, 0.25mm×30m, conditions: 40-230°C (2°C/min), injection temperature: 230°C). The signal was monitored with an MS detector.
  • 76
  • [ 53562-86-0 ]
  • [ 1510836-95-9 ]
  • {ONOMe,Cumyl}Al((R)-OCH(CH3)CH2COOCH3) [ No CAS ]
YieldReaction ConditionsOperation in experiment
In (2)H8-toluene at 20 - 80℃; for 15h; Inert atmosphere; Glovebox;
  • 77
  • [ 53562-86-0 ]
  • [ 1270043-91-8 ]
  • C22H34O7Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
73.7% With dmap In dichloromethane at 20℃;
  • 78
  • [ 53562-86-0 ]
  • [ 870-63-3 ]
  • (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhex-4-enoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% Stage #1: (S)-3-hydroxybutyric acid methyl ester With lithium diisopropyl amide In tetrahydrofuran at -30℃; for 1.75h; Stage #2: prenyl bromide In tetrahydrofuran; 1,2-dimethoxyethane at -78 - -60℃; for 2.75h; 1.1 Example 1, Step 1: Preparation of (S)-methyl2-((S)-1-hydroxyethyl)-5-methylhex-4-enoate Example 1, Step 1: Preparation of (S)-methyl2-((S)-1-hydroxyethyl)-5-methylhex-4-enoateTo a solution of diisopropylamine(19.93 milliliters (mL), 142 millimoles (mmol)) in anhydrous THF (99 mL) at -50 oc (deficient dry ice/acetone bath) was added n-butyllithium(n BuLi; 54.3 mL, 130 mmol, 2.5 Min hexanes). This solution was removed from the cold bath for 15minutes (min), then re-cooled to -50 °C. To the lithium diisopropylamide (LDA) was added a solution of(S)-methyl3-hydroxyhutanoate (6.64 ml, 59.3 mmol) in THF (20.0 mL) dropwise over15 min using a cannula.This solution vvas allowed to vaml to -30 oc over 30 rnin, stirred at -30 oc for 1 h, and recooledto -78 "C. To the enolate was added a solution of 1-bromo-3-methylhut-2-ene (13.7 mL, 119 mmol) in anhydrous1,2-dimethoxyethane (20.0 mL, 193 mmol) dropwise over 15 min. The cold bath was at -60 oc after 1 hat which time the reaction flask was removed from the bath and stirred without cooling for 1.5 h. The reactionwas quenched by the additionof sat aq.ammonium chloride (NHlCl; 50mL), diluted with EtOAc (50 mL), and the phases were separated.The aqueous phase was fmiherextracted with EtOAc (2 x 50 mL) and the combined organicextracts vvere washed with sataq. sodium chloride (NaCl, brine; 50 mL), dried over sodiumsuLfate Na2S04,filtered, and concentrated to dryness. The cmde residue was purified by flash column chromatogtraphy (120 gTams (g) silicagel (SiO2), 0-40 EtOAc/hexanes)to afford the title compound (9.5 g, 51.0 mmol, 86?) as a slightlyyellow oil: IR (thin film) 3452, 2971,2929, 1730, 1437, 1198, 1160 cm-1 1H NMR (400 MHz, CDCh) 8 5.11-5.01 (m, lH), 3.92(p, J = 6.3 Hz, lH), 3.70 (s, 3H), 2.78 (s, lH), 2.46-2.28 (m, 3H), L69 (d, J = 1.4 Hz, 3H), 1.62 (s, 3H), 1.23 (d, J'" 6.4 Hz, 3H); 13CNMR (101 MHz, CDCb) o 175.54, 134.14, 120.30,67.78, 52.72, 51.52,27.90, 25.73, 21.46, 17.64.
86% Stage #1: (S)-3-hydroxybutyric acid methyl ester With lithium diisopropyl amide In tetrahydrofuran at -30℃; for 1.75h; Stage #2: prenyl bromide In tetrahydrofuran; 1,2-dimethoxyethane at -78 - 60℃; for 2.5h; 1.1 Example 1, Step 1 : Preparation of (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhex-4-enoate Example 1, Step 1 : Preparation of (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhex-4-enoateTo a solution of diisopropylamine (19.93 milliliters (mL), 142 millimoles (mmol)) in anhydrous THF (99 mL) at -50 °C (deficient dry ice/acetone bath) was added n-butyllithium (n- BuLi; 54.3 mL, 130 mmol, 2.5 M in hexanes). This solution was removed from the cold bath for 15 minutes (min), then re-cooled to -50 °C. To the lithium diisopropylamide (LDA) was added a solution of (S)-methyl 3-hydroxybutanoate (6.64 ml, 59.3 mmol) in THF (20.0 mL) dropwise over 15 min using a cannula. This solution was allowed to warm to -30 °C over 30 min, stirred at -30 °C for 1 h, and recooled to -78 °C. To the enolate was added a solution of l-bromo-3-methylbut-2-ene (13.7 mL, 119 mmol) in anhydrous 1,2-dimethoxy ethane (20.0 mL, 193 mmol) dropwise over 15 min. The cold bath was at -60 °C after 1 h at which time the reaction flask was removed from the bath and stirred without cooling for 1.5 h. The reaction was quenched by the addition of sat. aq. ammonium chloride (NH4C1; 50 mL), diluted with EtOAc (50 mL), and the phases were separated. The aqueous phase was further extracted with EtOAc (2 x 50 mL) and the combined organic extracts were washed with sat. aq. sodium chloride (NaCl, brine; 50 mL), dried over sodium sulfate Na2SO4, filtered, and concentrated to dryness. The crude residue was purified by flash column chromatography (120 grams (g) silica gel (Si02), 0-^40% EtOAc/hexanes) to afford the title compound (9.5 g, 51.0 mmol, 86%) as a slightly yellow oil: IR (thin film) 3452, 2971, 2929, 1730, 1437, 1198, 1160 cm-1; 1H NMR (400 MHz, CDC13) δ 5.11 - 5.01 (m, 1H), 3.92 (p, J= 6.3 Hz, 1H), 3.70 (s, 3H), 2.78 (s, 1H), 2.46 - 2.28 (m, 3H), 1.69 (d, J= 1.4 Hz, 3H), 1.62 (s, 3H), 1.23 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.54, 134.14, 120.30, 67.78, 52.72, 51.52, 27.90, 25.73, 21.46, 17.64.
86% Stage #1: (S)-3-hydroxybutyric acid methyl ester With lithium diisopropyl amide In tetrahydrofuran at -78 - -30℃; for 1.75h; Stage #2: prenyl bromide In tetrahydrofuran; 1,2-dimethoxyethane at -60℃; for 2.75h; 1.1 Preparation of (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhex-4-enoate To a solution of diisopropylamine (19.9 milliliters (mL), 142 millimoles (mmol)) in anhydrous THF (99 mL) at-50° C. (deficient dry ice/acetone bath) was added n-butyllithium (n-l3uLi; 54.3 mL, 130 mmol, 2.5 M in hexanes). This solution was removed from the cold bath for 15 minutes (mm), then re-cooled to -50° C. To the LDA was added a solution of (S)-methyl 3-hydroxybutanoate (6.64 mL, 59.3 mmol) in THF (20.0 mL) dropwise over 15 mm using a cannula. This solution was allowed to warm to -30° C. over 30 mi stirred at -30° C. for 1 hour (h), and recooled to -78° C. To the enolate was added a solution of 1 -bromo-3-meth- ylbut-2-ene (13.7 mL, 119 mmol) in anhydrous 1,2- dimethoxyethane (20.0 mL, 193 mmol) dropwise over 15 mm. The cold bath was at -60° C. afier 1 hat which time the reaction flask was removed from the bath and the mixture stirred without cooling for 1.5 h. The reaction mixture was quenched by the addition of saturated (sat.) aqueous (aq.) ammonium chloride (NH4C1; 50 mL), diluted with EtOAc (50 mL), and the phases were separated. The aqueous phase was further extracted with EtOAc (2x50 mL) and the combined organic extracts were washed with sat. aq. sodium chloride (NaC1, brine; 50 mL), dried over sodium sulfate (Na2SO4), filtered, and concentrated to dryness. The crude residue was purified by flash column chromatography (silica gel (Si02), 040% EtOAc in hexanes) to afford the title compound (9.5 g, 86%) as a slightly yellow oil: IR (thin film) 3452, 2971, 2929, 1730, 1437, 1198, 1160 cm’; ‘H NMR (400 MHz, CDC13) ö 5.11-5.01 (m, 1H), 3.92 (p, J=6.3 Hz, 1H), 3.70 (s, 3H), 2.78 (s, 1H), 2.46-2.28 (m, 3H), 1.69 (d, J=1 .4Hz, 3H), 1.62 (s, 3H), 1.23 (d, J=6.4 Hz, 3H); ‘3C NMR (101 MHz, CDC13) ö 175.54, 134.14, 120.30, 67.78, 52.72, 51.52, 27.90, 25.73, 21.46, 17.64.
86% Stage #1: (S)-3-hydroxybutyric acid methyl ester With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -50 - -30℃; for 1.75h; Stage #2: prenyl bromide In tetrahydrofuran; 1,2-dimethoxyethane; hexane at -78 - 20℃; for 2.75h; 9.1 Example 9, Step 1: Preparation of (,S)-methyl 2-((S)-l -hydroxy ethyl)-5-methylhex-4- enoate: To a solution of diisopropylamine (19.9 mL, 142 mmol) in anhydrous THF (99 mL) at -50 °C was added -BuLi (54.3 mL, 130 mmol, 2.5 M in hexanes), and the resulting solution was removed from the cold bath for 15 min and then cooled back to -50 °C. To the freshly prepared LDA was added a solution of (,S)-methyl 3 -hydroxy butanoate (6.64 mL, 59.3 mmol) in THF (20.0 mL) dropwise over a 15 min period, and the mixture was allowed to warm to -30 °C over a 30 min period. The reaction mixture was stirred at -30 °C for 1 h, cooled to -78 °C, and the resulting enolate was treated with a solution of l-bromo-3-methylbut-2-ene (13.7 mL, 119 mmol) in anhydrous 1,2- dimethoxy ethane (20.0 mL, 193 mmol) dropwise over a 15 min period. The mixture was stirred between -60 °C and -70 °C for 1 h, and the reaction flask was removed from the bath and stirring continued as the mixture was warmed to room temperature over a period of 1.5 h. The reaction was quenched by the addition of sat'd aq NFLCl (50 mL) and extracted with EtOAc (50 mL). The phases were separated and the aq phase was further extracted with EtOAc (2 x 50 mL), and the combined organic extracts were washed with brine (50 mL), dried over Na2S04, filtered, and concentrated to dryness. The crude residue was purified by column chromatography (Si02; 0- 40% EtOAc in hexanes) to afford the title compound (9.5 g, 86%) as a slightly yellow oil: IR (Thin Film) 3452, 2971, 2929, 1730, 1437, 1198, 1160 cm"1; 1H NMR (400 MHz, CDC13) δ 5.11 - 5.01 (m, 1H), 3.92 (p, J= 6.3 Hz, 1H), 3.70 (s, 3H), 2.78 (s, 1H), 2.46 - 2.28 (m, 3H), 1.69 (d, J= 1.4 Hz, 3H), 1.62 (s, 3H), 1.23 (d, J= 6.4 Hz, 3H); 13C NMR (101 MHz, CDC13) δ 175.54, 134.14, 120.30, 67.78, 52.72, 51.52, 27.90, 25.73, 21.46, 17.64.
81% Stage #1: (S)-3-hydroxybutyric acid methyl ester With lithium diisopropyl amide In tetrahydrofuran at -70℃; for 1h; Inert atmosphere; Stage #2: prenyl bromide With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran at -70 - -10℃; for 3h; Inert atmosphere; diastereoselective reaction;

  • 79
  • [ 53562-86-0 ]
  • (S)-methyl 2-((S)-1-hydroxyethyl)-5-methylhexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1.75 h / -30 °C 1.2: 2.75 h / -78 - -60 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 20 h / 20 °C
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1.75 h / -30 °C 1.2: 2.5 h / -78 - 60 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 20 h / 20 °C
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1.75 h / -78 - -30 °C 1.2: 2.75 h / -60 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 20 h / 20 °C
Multi-step reaction with 2 steps 1.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.75 h / -50 - -30 °C 1.2: 2.75 h / -78 - 20 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 20 h / 20 °C / 760.05 Torr

  • 80
  • [ 53562-86-0 ]
  • (S)-methyl 2-((S)-1-((4-methoxybenzyl)oxy)ethyl)-5-methylhexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1.75 h / -30 °C 1.2: 2.75 h / -78 - -60 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 20 h / 20 °C 3.1: (1S)-10-camphorsulfonic acid / dichloromethane / 17 h / 0 - 20 °C
Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1.75 h / -30 °C 1.2: 2.5 h / -78 - 60 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 20 h / 20 °C 3.1: (1S)-10-camphorsulfonic acid / dichloromethane / 17 h / 0 - 20 °C
Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1.75 h / -78 - -30 °C 1.2: 2.75 h / -60 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 20 h / 20 °C 3.1: (1S)-10-camphorsulfonic acid / dichloromethane / 17 h / 0 - 20 °C
Multi-step reaction with 3 steps 1.1: diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1.75 h / -50 - -30 °C 1.2: 2.75 h / -78 - 20 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 20 h / 20 °C / 760.05 Torr 3.1: (1S)-10-camphorsulfonic acid / dichloromethane / 17 h / 0 - 20 °C

  • 81
  • methyl crotonate [ No CAS ]
  • [ 53562-86-0 ]
  • [ 3976-69-0 ]
YieldReaction ConditionsOperation in experiment
48 % ee With water In aq. phosphate buffer at 28℃; Enzymatic reaction; Overall yield = 40 %Chromat.; enantioselective reaction;
  • 82
  • [ 53562-86-0 ]
  • [ 870-63-3 ]
  • (S)-methyl 5-methyl-2-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)hex-4-enoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -70 °C / Inert atmosphere 1.2: 3 h / -70 - -10 °C / Inert atmosphere 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / dichloromethane / 14 h / 25 °C / Inert atmosphere
  • 83
  • 3-O-α-L-rhamnopyranosyl polygalacic acid {28-O-α-L-rhamnopyranosyl(1→3)-β-D-xylopyranosyl(1→4)-3-acetyl-α-L-rhamnopyranosyl(1→2)-4-O-[(3S)-3-[(3S)-3-[(3S)-3-hydroxy-1-oxobutoxy]-1-oxobuthoxy]-1-oxobutyl]-β-D-fucopyranosyl} ester [ No CAS ]
  • [ 124-41-4 ]
  • [ 53562-86-0 ]
  • [ 121340-61-2 ]
YieldReaction ConditionsOperation in experiment
1.4 mg In methanol at 20℃; for 3h; Deacylation of 1-7 General procedure: A solution of each perennisaponin (1-4: 2 mg each) in 0.5 % NaOMe-MeOH (1.0 mL) was stirred at room temperature for 3 h. An aliquot of the mixture was subjected to HPLC analysis [column: YMC-Pack ODS-AQ, 250 x 4.6 mm i.d.; mobile phase: MeOH-H2O (20:80, v/v); detection: optical rotation [Shodex OR-2 (Showa Denko K.K.)]; flow rate: 0.7 mL/min] to identify methyl (S)-(+)-3-hydroxybutyrate [tR 9.2 min (positive)], respectively, which was identified by comparison with a commercially obtained sample [a]D20 +41.3 (c = 0.32, CHCl3)} [15]. The remainder of each mixture was neutralized with Dowex HCR-W2 resin (H+ form), which was then removed by filtration. The filtrate was concentrated and the resulting product was purified by HPLC [Cosmosil 5C18-MS-II, CH3CN-MeOH-H2O (32:16:52, v/v/v)] to furnish bellissaponin BS1 (1a, 1.4 mg from 1; 1.3 mg from 2; 1,5 mg from 3; 1.5 mg from 4, respectively) [14].
  • 84
  • 3-O-α-L-rhamnopyranosyl polygalacic acid {28-O-α-L-rhamnopyranosyl(1→3)-β-D-xylopyranosyl(1→4)-3-acetyl-α-L-rhamnopyranosyl(1→2)-4-O-[(3S)-3-[(3S)-3-[(3S)-3-[(3S)-3-hydroxy-1-oxobutoxy]-1-oxobuthoxy]-1-oxobuthoxy]-1-oxobutyl]-β-D-fucopyranosyl} ester [ No CAS ]
  • [ 124-41-4 ]
  • [ 53562-86-0 ]
  • [ 121340-61-2 ]
YieldReaction ConditionsOperation in experiment
1.3 mg In methanol at 20℃; for 3h; Deacylation of 1-7 General procedure: A solution of each perennisaponin (1-4: 2 mg each) in 0.5 % NaOMe-MeOH (1.0 mL) was stirred at room temperature for 3 h. An aliquot of the mixture was subjected to HPLC analysis [column: YMC-Pack ODS-AQ, 250 x 4.6 mm i.d.; mobile phase: MeOH-H2O (20:80, v/v); detection: optical rotation [Shodex OR-2 (Showa Denko K.K.)]; flow rate: 0.7 mL/min] to identify methyl (S)-(+)-3-hydroxybutyrate [tR 9.2 min (positive)], respectively, which was identified by comparison with a commercially obtained sample [a]D20 +41.3 (c = 0.32, CHCl3)} [15]. The remainder of each mixture was neutralized with Dowex HCR-W2 resin (H+ form), which was then removed by filtration. The filtrate was concentrated and the resulting product was purified by HPLC [Cosmosil 5C18-MS-II, CH3CN-MeOH-H2O (32:16:52, v/v/v)] to furnish bellissaponin BS1 (1a, 1.4 mg from 1; 1.3 mg from 2; 1,5 mg from 3; 1.5 mg from 4, respectively) [14].
  • 85
  • 3-O-α-L-rhamnopyranosyl polygalacic acid {28-O-α-L-rhamnopyranosyl(1→3)-β-D-xylopyranosyl(1→4)-3-acetyl-α-L-rhamnopyranosyl(1→2)-4-O-[(3S)-3-(acetyloxy)-1-oxobutyl]-β-D-fucopyranosyl} ester [ No CAS ]
  • [ 124-41-4 ]
  • [ 53562-86-0 ]
  • [ 121340-61-2 ]
YieldReaction ConditionsOperation in experiment
1.5 mg In methanol at 20℃; for 3h; Deacylation of 1-7 General procedure: A solution of each perennisaponin (1-4: 2 mg each) in 0.5 % NaOMe-MeOH (1.0 mL) was stirred at room temperature for 3 h. An aliquot of the mixture was subjected to HPLC analysis [column: YMC-Pack ODS-AQ, 250 x 4.6 mm i.d.; mobile phase: MeOH-H2O (20:80, v/v); detection: optical rotation [Shodex OR-2 (Showa Denko K.K.)]; flow rate: 0.7 mL/min] to identify methyl (S)-(+)-3-hydroxybutyrate [tR 9.2 min (positive)], respectively, which was identified by comparison with a commercially obtained sample [a]D20 +41.3 (c = 0.32, CHCl3)} [15]. The remainder of each mixture was neutralized with Dowex HCR-W2 resin (H+ form), which was then removed by filtration. The filtrate was concentrated and the resulting product was purified by HPLC [Cosmosil 5C18-MS-II, CH3CN-MeOH-H2O (32:16:52, v/v/v)] to furnish bellissaponin BS1 (1a, 1.4 mg from 1; 1.3 mg from 2; 1,5 mg from 3; 1.5 mg from 4, respectively) [14].
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