* 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.
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 6.5 h; Stage #2: With toluene-4-sulfonic acid In dichloromethane at 20℃; for 48 h;
To a cold (0°C) solution of (S)-4-Hydroxy-1-methoxy-1-oxobutan-2-aminium chloride (3.5 gm, 21 mmol), suspended in dichloromethane (42 mL) added (Boc)2O(5.06 gm, 23.19 mmol) followed by addition of DIPEA (7.35 mL, 42.17 mmol). The reaction mixture was stirred at 0°C for 30 min and then allowed to stir for 6 hr at room temperature. Purification by silica gel flash column chromatography (EtOAc : Hexane – 1 : 4) yielded the desired product as a mixture of Methyl (tert-butoxycarbonyl)-L-homoserinate and (S)-tert-Butyl(2-oxotetrahydrofuran-3-yl)carbamate (4 gm, 17.13 mmol, 81percent) (TLC: EtOAc– Rf= 0.6, 0.56). Lactone was synthesized by treating the mixture of Methyl (tert-butoxycarbonyl)-L-homoserinate and (S)-tert-Butyl (2-oxotetrahydrofuran-3-yl)carbamate (12) (500 mg, 2.15 mmol) with p-TsOH (123 mg, 0.642 mmol) in dry DCM (35 mL) at room temperature for 48 hrs.Purification by silica gel flash column chromatography (EtOAc : Hexane – 1 : 4)yielded the desired product as a white solid(397 mg, 1.98 mmol, 92percent) (TLC: EtOAc– Rf = 0.6). IR (NaCl,neat): 3365, 2980, 2935, 1778, 1687, 1531, 1456, 1369, 1295, 1269, 1253, 1221,1163, 1107, 1066, 1016, 1001, 979, 950 cm-1; IR (NaCl, 10 mM in CHCl3): 3464, 3433,3026, 3010, 2982, 2934, 2917, 2884, 1785, 1715, 1504, 1371, 1292, 1218, 1161,1081, 864, 783, 703 cm-1; H NMR (400 MHz, CDCl3) δ ppm: 5.04 (bs,1H), 4.45 (t, J = 9.2 Hz, 1H), 4.34(bs, 1H), 4.28-4.21 (m, 1H), 2.79-2.72 (m, 1H), 2.24-2.13 (m, 1H), 1.46 (s,9H); C NMR (100 MHz, CDCl3) δ ppm: 175.4, 155.4, 80.4, 65.7, 50.0, 30.3, 28.2; HRMS m/zCalcd for C9H15NO4Na 224.0899, Found 224.0896.
Reference:
[1] European Journal of Organic Chemistry, 2007, # 30, p. 5050 - 5058
10
[ 128427-10-1 ]
[ 40856-59-5 ]
[ 104227-71-6 ]
Reference:
[1] Journal of the American Chemical Society, 2015, vol. 137, # 11, p. 3767 - 3770
[2] Journal of the American Chemical Society, 2015, vol. 137, # 11, p. 3767 - 3770
11
[ 24424-99-5 ]
[ 77856-40-7 ]
[ 40856-59-5 ]
Reference:
[1] Synthesis, 1996, # 1, p. 39 - 41
12
[ 34619-03-9 ]
[ 2185-02-6 ]
[ 40856-59-5 ]
Reference:
[1] Chemical Communications, 2011, vol. 47, # 1, p. 385 - 387
13
[ 24424-99-5 ]
[ 40856-59-5 ]
Reference:
[1] Journal of Organic Chemistry, 1986, vol. 51, # 26, p. 5047 - 5050
[2] Synthesis, 1991, # 7, p. 526 - 528
[3] Tetrahedron Letters, 1987, vol. 28, # 31, p. 3605 - 3608
14
[ 63-68-3 ]
[ 24424-99-5 ]
[ 40856-59-5 ]
Reference:
[1] Journal of Organic Chemistry, 2008, vol. 73, # 8, p. 3212 - 3217
Reference:
[1] Journal of the American Chemical Society, 2015, vol. 137, # 11, p. 3767 - 3770
[2] Journal of the American Chemical Society, 2015, vol. 137, # 11, p. 3767 - 3770
A solution of 2-fluoro-4-iodoaniline (7.11g) in anhydrous DCM (40ml) under N2 at 0C was treated dropwise with trimethylaluminium (2N in heptane; 15ml). The mixture was allowed to stir for SOmin before a solution of 1,1-dimethylethyl [(3S)-2-oxotetrahydro-3-furanyl]carbamate (5.03g), in anhydrous DCM (35ml), was added dropwise. The reaction was allowed to warm up to ambient temperature and stirred for 18h, before quenching with 10% aqueous citric acid (10ml). Saturated aqueous potassium sodium tartrate (100ml) was then added with stirring followed by separation of the organic and aqueous layers. The organic layer was dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using Biotage chromatography (silica, eluting with cyclohexane:ethyl acetate 3:2) to afford an off-white solid which was an inseparable mixture (c. 1:2) of the starting material and the title compound (5.55g). Mass spectrum: Found: MH+ 439
Step A Preparation of (S)-N-(tert-butoxycarbonyl)homoserine lactone To a solution of (S)-homoserine lactone hydrochloride (11.0 g, 79.9 mmol) and di-tert-butylpyrocarbonate (19.2 g, 88.0 mmol) in 160 mL of dichloromethane at 0 C. was added diisopropylethylamine (13.9 mL, 79.9 mmol) over 3 min. The solution was allowed to warm to room temperature. After 3 hours, another portion of di-tert-butylpyrocarbonate (1.75 g, 8.0 mmol) and dilsopropylethylamine (0.70 mL, 4.0 mmol) were added, and the mixture was stirred for an additional 2.5 hours. The solution was washed with 10% citric acid, sat. NaHCO3, and brine, dried (Na2 SO4), filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography (50% EtOAc/hexane) to provide pure titled compound.
Step E (S)-N-(tert-butoxycarbonyl)homoserine lactone To a solution of (S)-homoserine lactone hydrochloride (11.0 g, 79.9 mmol) and di-tert-butylpyrocarbonate (19.2 g, 88.0 mmol) in 160 mL of dichloromethane at 0 C. was added diisopropyl-ethylamine (13.9 mL, 79.9 mmol) over 3 min. The solution was allowed to warm to room temperature. After 3 hours, another portion of di-tert-butylpyrocarbonate (1.75 g, 8.0 mmol) and diisopropylethylamine (0.70 mL, 4.0 mmol) were added, and the mixture was stirred for an additional 2.5 hours. The solution was washed with 10% citric acid, sat. NaHCO3, and brine, dried (Na2 SO4), filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography (50% EtOAc/hexane) to provide pure titled compound.
61
[ 40856-59-5 ]
[ 912846-41-4 ]
Yield
Reaction Conditions
Operation in experiment
Intermediate 13 EPO <DP n="41"/>1.1-Dimethylethyl ((1S)-3-hvdroxy-1-fr(2-methyl-1.2,3.4-tetrahvdro-6- isoquinolinvDaminolcarbonvDpropyDcarbamate; A solution of trimethylaluminium (2M in heptane, 1.4 ml) was added dropwise to a solution of 6-amino-2-methyl-1 ,2,3,4-tetrahydro-isoquinoline (0.4g) in DCM (15ml) at ambient temperature under nitrogen. After reaction for 30min, 1 ,1-dimethylethyl [(3S)-2- oxotetrahydro-3-furanyl]carbamate (0.496g) was added in a further 15ml of DCM and the reaction stirred at ambient temperature for 14h. The solution was quenched with 50ml of 10% aqueous sodium potassium tartrate and the DCM layer passed through a hydrophobic frit, followed by a second DCM extraction. The volume was reduced and the solution applied to a 2Og silica SPE cartridge, eluted with a gradient of cyclohexane:ethyl acetate (1 :1 to neat), then 10%-20% MeOH in chloroform (+0.5% 0.88 ammonia), affording the title compound (0.147g) as a colourless oil. Mass spectrum: Found: MH+ 364 H.p.l.c. Rt 1.76min
A solution of 2-fluoro-4-iodoaniline (7. 11g) in anhydrous DCM (40ML) under N2 at 0C was treated dropwise with trimethylaluminium (2N in heptane; 15ml). The mixture was allowed to stir for 30min before a solution of <strong>[40856-59-5]tert-butyl (3S)-2-oxotetrahydrofuran-3-ylcarbamate</strong> (5.03g), in anhydrous DCM (35ml), was added dropwise. The reaction was allowed to warm up to ambient temperature and stirred for 18h, before quenching with 10% aqueous citric acid acid (10ml) Saturated aqueous potassium sodium tartrate (100ml) was then added with stirring followed by separation of the organic and aqueous layers. The organic layer was dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was purified using BIOTAGE TM CHROMATOGRAPHY (SILICA, ELUTING with cyclohexane : ethyl acetate 3: 2) to afford an off-white solid which was an inseparable mixture (c. 1: 2) of the starting material and the title compound (5.55g). Mass spectrum: Found: MH+ 439
A solution of 2-fluoro-4-iodoaniline (7. 11G) in anhydrous DCM (40ml) under N2 at 0C was treated dropwise with trimethylaluminium (2N in heptane; 15MI). The mixture was allowed to stir for 30min before a solution of <strong>[40856-59-5]tert-butyl (3S)-2-oxotetrahydrofuran-3-ylcarbamate</strong> (5. 03G), in anhydrous DCM (35ml), was added dropwise. The reaction was allowed to warm up to ambient temperature and stirred for 18h, before quenching with 10% aqueous citric acid acid (10ml) Saturated aqueous potassium sodium tartrate (100MOI) was then added with stirring followed by separation of the organic and aqueous layers. The organic layer was dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using BIOTAGE TM CHROMATOGRAPHY (SILICA, ELUTING with cyclohexane : ethyl acetate 3: 2) to afford an off-white solid which was an inseparable mixture (c. 1: 2) of the starting material and the title compound (5.55g). Mass spectrum: Found: MH+ 439
A solution of 2-fluoro-4-iodoaniline (7.11g) in anhydrous DCM (40ml) under nitrogen at5 0C was treated dropwise with trimethylaluminium (2N in heptane; 15ml). The mixture was allowed to stir for 30min before a solution of 1,1-dimethylethyl [(3S)-2-oxotetrahydro-3-furanyl]carbamate (5.03g), in anhydrous DCM (35ml), was added dropwise. The reaction was allowed to warm up to ambient temperature and stirred for 18h, before quenching with 10% aqueous citric acid (10ml). Saturated aqueous potassium sodium tartrate3 (100ml) was then added with stirring followed by separation of the organic and aqueous layers. The organic layer was dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using Biotage chromatography (silica, eluting with cyclohexane:ethyl acetate 3:2) to afford an off-white solid which was an inseparable mixture (c. 1:2) of the starting material and the title compound (5.55g).Mass spectrum: Found: MH+ 439
A solution of Intermediate 2 (5.53g) in anhydrous DCM (40ml) at room temperature under nitrogen was treated dropwise over 35min with trimethyl aluminium (2 molar in heptane, 13. 5ML). Slow addition rate and a water bath were used to prevent reaction temperature rising above 30C during addition. The mixture was stirred for 30min then treated with a solution of 1, 1-dimethylethyl [ (3S)-2-OXOTETRAHYDRO-3-FURANYL] carbamate (3.87g) in anhydrous DCM (40MUT), and the final mixture stirred for 20h before quenching by cautious addition of 5% citric acid solution (100ML). A fine pricipitate formed, this was filtered through a pad of celite filteraid, washed with water (50MI) and DCM (100MOI). The combined filtrates were partitioned, the aqueous layer extracted with DCM (50MOI), and the combined organic layers were washed with saturated sodium potassium tartrate solution (Rochelle's Salt) (50ml), brine (50ML) then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a crude yellow oil (7.45g). Purification by Quad BIOTAGE CHROMATOGRAPHY (2 x 90g Si) eluting with 1% MeOH in DCM gave the title compound (2. 11G) as a pale yellow foam. Mass spectrum: Found: MH+447 H. p. l. c. Rt 3.27min
A solution of Intermediate 10 (5.53g) in anhydrous DCM (40MOI) at room temperature under nitrogen was treated dropwise over 35min with trimethyl aluminium (2 molar in heptane, 13. 5ML). Slow addition rate and a water bath were used to prevent reaction temperature rising above 30C during addition. The mixture was stirred for 30min then treated with a solution of 1, 1-dimethylethyl [ (3S)-2-OXOTETRAHYDRO-3-FURANYL] carbamate (3.87g) in anhydrous DCM (40ML), and the final mixture stirred for 20h before quenching by cautious addition of 5% citric acid solution (100MUT). A fine precipitate formed, this was filtered through a pad of celite filteraid, washed with water (50ML) and BCM (100ML). The combined filtrates were partitioned, the aqueous layer extracted with DCM (50MOI), and the combined organic layers were washed with saturated sodium potassium tartrate solution (Rochelle's Salt) (50ml), brine (50ML) then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a crude yellow oil (7.45g). Purification by Quad BIOTAGET" CHROMATOGRAPHY (2 x 90g Si) eluting with 1% methanol in DCM gave the title compound (2. 11G) as a pale yellow foam. Mass spectrum: Found: MH+ 447 H. p. l. c. Rt 3.27min
A solution of Intermediate 20 (0.74g) in dry DCM (20ml) was stirred at ambient temperature under nitrogen and treated with a 2M solution of trimethylaluminium in heptane (2.5ml) over 15 min. The reaction mixture was stirred at 25-27C for 15 min. A0 solution of 1,1-dimethylethyl [(3S)-2-oxotetrahydro-3-furanyl]carbamate (0.817g) in dry DCM (5ml) was added over 15 min. The reaction mixture was stirred at ambient temperature, under nitrogen for 19h. The reaction mixture was treated with 10% aqueous sodium potassium tartrate (15ml) over 30 min and filtered through a hydrophobic frit. The aqueous layer was stirred with DCM (50ml) and filtered through the hydrophobic frit. The5 combined DCM extracts were concentrated under reduced pressure. The residue waspurified by silica SPE eluting with DCM:methanol:2N methanolic ammonia 100:10:1 togive the title compound (0.86g) as a cream foam.Mass spectrum: Found: MH+ 384
A solution of Intermediate 27 (0.374g) in DCM (4ml) was degassed at 10C in an ice bath. Trimethylaluminium (1.12ml, 2M in heptane) was added dropwise below 20C and the mixture was stirred for SOmin at ambient temperature. A solution of 1,1-dimethylethyl [ (3S)-2-oxotetrahydro-3-furanyl]carbamate (0.38g) in DCM (4ml) was added dropwise below 25C. The mixture was stirred at ambient temperature for 20h. A further portion of trimethylaluminium (1.12ml, 2M in heptane) was added and the mixture was heated at reflux for 2h. The mixture was cooled in an ice bath and then 10% aqueous sodium potassium tartrate (7ml) was added dropwise over 10min. The mixture was diluted with DCM. The separated organic layer was passed through a hydrophobic frit andconcentrated under reduced pressure. The residue was purified using Biotagechromatography (silica, gradient eluting with chloroform:methanol, 9:1 tochloroform:methanol: aqueous ammonia, 9:1:1%) to give the title compound (0.635g) as awhite solid.Mass spectrum: Found: MH* 402H.p.l.c. Rt1.84min.
With sodium tetrahydroborate; In tetrahydrofuran; at 0 - 5℃; for 2h;
Tn a reactor a suspension of NaBH4 (17.5 g) in THF (202 mL) is prepared and cooled at0-5C. A solution of L-boc-aspartic anhydride (50 g) in THF (300 mL) is added dropwise keeping the temperature below 5C. Thereafter the reaction mixture is stined for additional 2 h at 0-5C until complete conversion is achieved and then it is quenched by dropwise addition to 50 mL of water cooled at 0-5C. The resulting mixture is stirred at 10-20C for 30 mm then thepH is adjusted from 10.3 to 3.5-4.0 by addition of a 30% aqueous solution of citric acid. THF is distilled off under vacuum and the residue is dissolved in ethyl acetate (250 mL), the organic phase is separated and the aqueous phase extracted with ethyl acetate. The combined organic phases are washed with brine and then concentrated in vacuo. After addition of toluene (250 mL) to the residue water is removed by azeotropic distillation, ethyl acetate (250 mL) and sodiumbicarbonate 10% solution are added. After separation and drying, the organic phase is concentrated under vacuum and then precipitation is completed by addition of n-heptane. After stirnng at 20-25C and at 0-5C the solid is filtered off, washed with n-heptane and finally dried under vacuum at 50C. The product is a white powder 36.5 g (80% yield) and consists of a 80:20 mixture of the two regioisomers 3S- and 2S- of Boc-(S)-amino-y-butyrolactone). The ee of thedesired 3S isomer is 98%. Typical ?H-NMR signals (DMSO-d6) for the 3S isomer at 2.80 ppm (dd, 1H) and 7.45 ppm (bs, e-Boc), for the 2S isomer at 2.15 ppm (m, 1H) and 7.35 ppm (d, NHBoc).
tert-butyl (S)-(1-(2,4-dimethylphenyl)-4-hydroxy-1-oxobutan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
In an oven-dried flask, dried halogen-group-containing compounds (2.3 equiv) were added to dry THF containing magnesium metal (Mg) (2.3 equiv, with glass pieces to activate the magnesium metal) at room temperature under nitrogen. The reaction mixture was stirred vigorously until Grignard generation occurred. The lactone (1 equiv dissolved in 40 mL of THF) was added dropwise to the Grignard reagent solution, and the mixture was stirred at room temperature for 16 h and monitored by TLC. The mixture was treated with saturated aqueous NH4Cl (20 mL) and then extracted with AcOEt (3×10mL). The combined organic phases were dried over Na2SO4 and the solvent was removed by an evaporator. The residue was purified by silica-gel column chromatography (AcOEt/hexane). In another experiment, the ring-opening reactions of homoserine lactone with select Grignard reagents were carried out using 2.7 equiv ArMgBr at r.t. and 50C for 2 h. 4.5 tert-Butyl (S)-(1-(2,4-dimethylphenyl)-4-hydroxy-1-oxobutan-2-yl)carbamate 6g Yellow viscous liquid, Rf = 0.3 (30% AcOEt/hexane) [alpha]D20 = -3.6 (c 1, CH2Cl2) 1H NMR (400 MHz, CDCl3): delta = 7.68 (d, J = 8.0 Hz, 1H), 7.15-7.09 (m, 2H), 5.85 (d, J = 7.0 Hz, 1H), 5.44-5.40 (m, 1H), 3.95 (brs, 1H), 3.72-3.69 (m, 2H), 2.49 (s, 3H), 2.38 (s, 3H), 2.26-2.24 (m, 1H), 1.46 (s, 9H), 146-1.43 (m, 1H). 13C NMR (100 MHz, CDCl3): delta = 201.2, 157.2, 143.2, 140.1, 133.3, 131.6, 129.7, 126.9, 80.5, 58.4, 54.0, 37.0, 28.5, 28.3, 20.9. IR (neat, cm-1): 3416, 2975, 2929, 1679, 1612, 1492. HRMS (ESI) m/z calc. for C17H25NO4: 306.1783, found: 306.1705.
In an oven-dried flask, dried halogen-group-containing compounds (2.3 equiv) were added to dry THF containing magnesium metal (Mg) (2.3 equiv, with glass pieces to activate the magnesium metal) at room temperature under nitrogen. The reaction mixture was stirred vigorously until Grignard generation occurred. The lactone (1 equiv dissolved in 40 mL of THF) was added dropwise to the Grignard reagent solution, and the mixture was stirred at room temperature for 16 h and monitored by TLC. The mixture was treated with saturated aqueous NH4Cl (20 mL) and then extracted with AcOEt (3×10mL). The combined organic phases were dried over Na2SO4 and the solvent was removed by an evaporator. The residue was purified by silica-gel column chromatography (AcOEt/hexane). In another experiment, the ring-opening reactions of homoserine lactone with select Grignard reagents were carried out using 2.7 equiv ArMgBr at r.t. and 50C for 2 h.
In an oven-dried flask, dried halogen-group-containing compounds (2.3 equiv) were added to dry THF containing magnesium metal (Mg) (2.3 equiv, with glass pieces to activate the magnesium metal) at room temperature under nitrogen. The reaction mixture was stirred vigorously until Grignard generation occurred. The lactone (1 equiv dissolved in 40 mL of THF) was added dropwise to the Grignard reagent solution, and the mixture was stirred at room temperature for 16 h and monitored by TLC. The mixture was treated with saturated aqueous NH4Cl (20 mL) and then extracted with AcOEt (3×10mL). The combined organic phases were dried over Na2SO4 and the solvent was removed by an evaporator. The residue was purified by silica-gel column chromatography (AcOEt/hexane). In another experiment, the ring-opening reactions of homoserine lactone with select Grignard reagents were carried out using 2.7 equiv ArMgBr at r.t. and 50C for 2 h.
In an oven-dried flask, dried halogen-group-containing compounds (2.3 equiv) were added to dry THF containing magnesium metal (Mg) (2.3 equiv, with glass pieces to activate the magnesium metal) at room temperature under nitrogen. The reaction mixture was stirred vigorously until Grignard generation occurred. The lactone (1 equiv dissolved in 40 mL of THF) was added dropwise to the Grignard reagent solution, and the mixture was stirred at room temperature for 16 h and monitored by TLC. The mixture was treated with saturated aqueous NH4Cl (20 mL) and then extracted with AcOEt (3×10mL). The combined organic phases were dried over Na2SO4 and the solvent was removed by an evaporator. The residue was purified by silica-gel column chromatography (AcOEt/hexane). In another experiment, the ring-opening reactions of homoserine lactone with select Grignard reagents were carried out using 2.7 equiv ArMgBr at r.t. and 50C for 2 h.