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CAS No. : | 102308-32-7 | MDL No. : | MFCD00209557 |
Formula : | C11H19NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PNJXYVJNOCLJLJ-MRVPVSSYSA-N |
M.W : | 229.27 | Pubchem ID : | 179824 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.82 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 62.72 |
TPSA : | 55.84 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.97 cm/s |
Log Po/w (iLOGP) : | 2.2 |
Log Po/w (XLOGP3) : | 1.02 |
Log Po/w (WLOGP) : | 1.18 |
Log Po/w (MLOGP) : | 0.22 |
Log Po/w (SILICOS-IT) : | 0.95 |
Consensus Log Po/w : | 1.11 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.64 |
Solubility : | 5.25 mg/ml ; 0.0229 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.78 |
Solubility : | 3.78 mg/ml ; 0.0165 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.18 |
Solubility : | 15.3 mg/ml ; 0.0667 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.18 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With diisobutylaluminium hydride; In toluene; at -78℃;Schlenk technique; | To a cooled (-78 C) solution of (S)-2,2-dimethyl-oxazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 4-methyl ester (2 g, 7.7 mmol) in dry toluene (20 mL) in a Schlenk flask was added dropwise 1 M standard solution of diisobutylaluminum hydride in toluene (13.3 mL). The reaction mixture was stirred for 2 h at -78 C. Then the reaction was quenched by adding slowly methanol (5 mL) cooled to -78 C. The resulting white emulsion was slowly poured into ice-cold 1 M HCl (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (2 x 50 mL) and water (50 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (hexane - ethyl acetate v/v 9 : 1) and 1.5 g (85%) of a colorless oil was isolated. 1H and 13C NMR spectra were consistent with literature data.5 IR (ATR, cm-1) nu: 3018, 2978, 1697, 1368, 1168, 1095; 1H NMR (400 MHz, CDCl3, rotamers) delta: 9.61 (d, J = 0.8 Hz, 0.4H, CHO), 9.55 (d, J = 2.4 Hz, 0.6H, CHO), 4.34 (m, 0.4H, CH-N), 4.19 (m, 0.6H, CH-N), 4.08 (m, 2H, CH2-O), 1.65 (s, 1.7H), 1.60 (s, 1.3H), 1.56 (s, 2H), 1.51 (s, 4.5H), 1.43 (s, 5.5H) 13C NMR (100 MHz, CDCl3, minor rotamer marked with *) delta: 199.4, 152.6*, 151.3, 95.1, 94.3*, 81.4*, 81.1, 64.7, 63.9, 63.4*, 28.3, 26.7*, 25.8, 24.7*, 23.8; MS (ESI) m/z: [M+Na]+ 252. |
With diisobutylaluminium hydride; In toluene; at -78 - 70℃; for 1h;Cooling with acetone-dry ice; | A 3-necked, 1000 mL round-bottom flask fitted with a N2 inlet adapter, magnetic stir bar, drying tube, temperature guage, and a septa was charged with methyl (S)- (-)-3- (TERT-BUTOXYCARBONYL)-2, 2-DIMETHYL-4-OXAZOLIDINE-CARBOXYLATE (15. 42 g, 59.46 mmole) and 120 ML of anhydrous toluene. The solution was cooled TO-78 C in A dry ice/acetone bath. A solution of DIISOBUTYLALUMINUM hydride in toluene (69.5 ML, 104.1 mmole) was cooled TO-78 C in A separate dry ice/acetone bath and added to the ester solution under N2 pressure via a steel cannula over a period of 30 min. The rate of addition was adjusted to prevent the reaction mixture from warming above- 70 C. After addition was complete, the mixture was stirred at-78 C for an additional 30 minutes. Excess hydride was quenched by the dropwise addition of 20 mL of pre-chilled (-78 C) methanol, again keeping the reaction temperature below- 70 C. The resulting white slurry was poured into 500 mL of ice-cold 1 N HC1. The aqueous layer was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with 300 mL 1 N HC1, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield (S)-4- formyl-2,2-dimethyl-3-oxazolidinecarboxylic acid tert-butyl ester (14.65 g) as a yellow oil. The residue was dissolved in 200 mL of anhydrous methanol, and the flask was flushed with N2. N-Benzylglycine ethyl ester (23.0 g, 118. 9 mmole) and acetic acid (6. 8 mL, 118. 9 mmole) were added, and the reaction mixture was cooled in an ice bath. A solution of sodium cyanoborohydride in tetrahydrofuran (100 mL, 100 mmole) was added via a cannula under positive N2 pressure. The reaction mixture was stirred at room temperature for 18h. A large excess of solid K2C03 was added until gas evolution ceased. The slurry was concentrated almost to dryness under reduced pressure and the residue was dissolved in 300 mL of dichloromethane. The organic layer was washed with 300 mL of 1: 1: 1 water/saturated NAHC03/BRINE. The aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, gradient: 15% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave 16.83 g (70%) of (S)-4-[(BENZYLETHOXYCARBONYL-METHYLAMINO)- methyl] -2, 2-dimethyl-3-oxazolidinecarboxylic acid tert-butyl ester as a clear viscous oil. MS : 407. 3 (M+1). | |
With diisobutylaluminium hydride; | Referring to FIG. 12, the synthesis of D-threo-PPMP may be via stereoselective addition of phenyl cuprate to D-Gamer aldehyde. The syn adduct, which leads to the D-threo isomer, will be the major product. The minor L-erythro isomer (approximately 5%) can be removed by crystallization from chloroform at the late stage of the synthesis. Synthesis starts with a four-step synthetic procedure for the production of D-Garner Aldehyde from D-serine. We have synthesized L-Gamer Aldehyde from L-serine at the kilogram scale utilizing the same method for the production of safingol. Garner Aldehyde was obtained in 28% overall yield at 98+% ee purity without chromatography. Phenyl cuprate will be generated in situ by the reaction of copper(I) iodide and phenyl magnesium bromide. The addition of phenyl cuprate to D-Garner Aldehyde will yield intermediate 6. The deprotection of intermediate 6 with HCl produces D-threo-1-phenyl-2-amino-propane-1,3-diol-7. The intermediate 7 is reacted with activated palmitic acid and followed by base hydrolysis to form intermediate 8. The primary hydroxy group of intermediate 8 will be converted to the mesylate, and then substituted with morpholine to yield the final product D-threo-PPMP. Our synthetic plan is an efficient, practical synthesis to the enantiomerically pure PPMP. Most of the reactions described have been successfully conducted at the kilogram scale in our kilo lab. It is anticipated that the initial 2 g bach can be delivered within 6 to 8 weeks after the desired PPMP enantiomer is identified. Modifications to the current method of synthesis and other methods of synthesis of D-threo-PPMP are readily known to one of skill in the art. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hexamethylsilazane at -84℃; | |
88% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium carbonate In toluene at -13℃; for 0.25h; Inert atmosphere; Stage #2: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester In toluene at -13℃; Inert atmosphere; | |
With 18-crown-6 ether; potassium hydride; 1,1,1,3,3,3-hexamethyl-disilazane THF, -78 deg C; Multistep reaction; |
With 18-crown-6 ether; potassium hydride; 1,1,1,3,3,3-hexamethyl-disilazane 1.) THF, -78 deg C, 10 min, 2.) THF, -78 deg C, 30 min; Multistep reaction; | ||
96 % ee | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester With 18-crown-6 ether In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; enantioselective reaction; | 2 (S,Z)-tert-Butyl 4-(3-methoxy-3-oxoprop-1-enyl)-2,2-dimethyloxazolidine-3-carboxylate (S,Z)-2 General procedure: To an oily suspension of NaH 60% (2.1g, 52.5mmol) in THF (90mL), at 0°C, under nitrogen was added, dropwise, a solution of (CF3CH2O)2P(O)CH2CO2Me (10mL, 52.3mmol) in THF (60mL). The solution was stirred at 0°C for 30min and then cooled to -78°C. To this solution was added 18-Crown-6 (69g, 261mmol) in THF (150mL) and then (R)-Garner’s aldehyde 1 (9.2g, 40.2mmol) in THF (20mL). The reaction mixture was stirred at the same temperature for 2h and the reaction quenched with aqueous saturated NH4Cl solution. The reaction mixture was extracted with Et2O, dried over MgSO4, and concentrated under vacuum. The crude residue was purified by column chromatography (silica gel, hexanes/Et2O:(1/4)) to give product (S,Z)-2 as white solid. Yield (9.39g, 82%). TLC (hexane/Et2O:1/1): Rf=0.71. HPLC (CH3CN/H2O:50/50, 0.7mL/min): tR=9.5min. 1H NMR (250MHz, CDCl3) δ (ppm) 6.22 (m, 1H, CH=CH-COOMe), 5.78 (d, 3JH-H=11.4Hz, 1H, CH=CH-COOMe), 5.34 (s, 1H, CH-α), 4.23 (t, 3JH-H=7.8Hz, 1 H, CH2aO), 3.71 (dd, 3JH-H=9.2 and 4JH-H=3.1Hz, 1H, CH2bO), 3.65 (s, 3H, COOCH3), 1.57 (s, 3H, C-CH3), 1.50-1.22 (m, 12H, C-CH3 and [C(CH3)3] Boc). 13C NMR (63MHz, CDCl3) δ (ppm) 166.25 (COOMe), 152.26 (CO Boc), 151.86/151.24 (rotamers, CH=CH-COOMe), 119.67/119.08 (rotamers, CH=CH-COOMe), 94.42/93.89 (rotamers, C-(CH3)2), 80.54/79.92 (rotamers, ([C(CH3)3]Boc), 69.03/68.80 (rotamers, CH2O), 56.61/55.58 (rotamers, CH-α), 51.38 (COOCH3), 28.34 ([C(CH3)3] Boc), 27.32/26.62 (rotamers, C-CH3), 24.92/23.75 (rotamers, C-CH3). The enantiomeric excess of (S,Z)-2 was determined by HPLC (Chiral OD-H column, i-PrOH/hexane:5/95), tR=7.8min for (R) enantiomer and tR=8.5min for (S) enantiomer in the HPLC chromatogram. The ee for (S,Z)-2 was 94% and its [α]25D[α]D25 -27.3 (c=0.91, CHCl3). For (R,Z)-2 enantiomer the ee=96% and the measured [α]25D[α]D25 +28.5 (c=1.03, CHCl3). LRMS-(ESI+), m/z: 286.2 [M+H]+, 308.1 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; | |
With potassium <i>tert</i>-butylate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Methyltriphenylphosphonium bromide (32.0 g, 89.5 mmol, 1.95 equiv) was azeotroped with benzene then suspended in THF (755 mL) at rt and potassium hexamethyldisilazide (0.5 M in toluene 172 mL, 86 mmol, 1.9 equiv) was added. The yellow suspension was stirred at rt for 1 h, then cooled to -78 C and the aldehyde 26 (10.5 g, 45.8 mmol) in THF (150 mL) was added. The cooling bath was removed and the mixture was stirred for 2 h. Methanol (75.5 mL) was added and the mixture was poured into saturated aqueous potassium sodium tartrate and water (1:1, 1500 mL). Following extraction with ether (2*1500 mL) and drying (MgSO4), the mixture was concentrated under reduced pressure. Chromatography (ethyl acetate: light petroleum=1: 9) gave the known alkene 27 (9.4 g, 90%). This alkene 27 was dissolved in aqueous hydrogen chloride (6 M, 31 mL, 186 mmol, 4.5 equiv) and the solution stirred at rt for 30 min. Concentration under reduced pressure gave the title compound 28 (4.6 g, 90%) as a waxy white solid, [alpha]D20 -11.0 (c 1.97, MeOH), {lit.8 .[alpha]D20 +12.9 (2S)-enantiomer (c 0.54, MeOH)}; numax/cm-1 3387, 3014, 2934, 2895, 1608, 1509, 1429, 1354, 1243, 1154, 1052, 993 and 950; deltaH (300MHz, CD3OD) 3.59 (1H, m, 2-H), 3.73-3.81 (2H, m, 1-H2), 5.43 (1H, d, J 10.8Hz, 4-H), 5.47 (1H, d, J 17.5Hz, 4-H?) and 5.89 (1H, ddd, J 7.3, 10.8, 17.5Hz, 3-H); deltaC (75MHz, CD3OD) 56.7, 63.0, 121.5 and 132.4; m/z (ES+) 88 (M+-35, 100%). | |
70% | With n-butyllithium; In tetrahydrofuran; hexane; at 0 - 20℃; for 4.4h;Inert atmosphere; | n-BuLi (2M in hexane, 1.7mL, 3.45 mmol, 1.5 eqv.) was added to a stirred suspension o fmethyltriphenylphosphonium bromide (1.23 g, 3.45 mmol, 1.5 eqv.) in dry THF (10 mL) under argon at 0C dropwise over 5 min, and the resulting solution was allowed to stir for 20 min at 0C. A solution of the aldehyde 3 (528 mg, 2.30 mmol) in THF (5 mL) was then added dropwise over 5 min with stirring at the same temperature. After 20 min, the solution was allowed to come to room temperature and was stirred for another 4 h. The reaction mixture was quenched by addition of aqueous NH4Cl solution (3 mL) and then extracted with ethyl acetate (250 mL).The combined organic extract was washed successively with H2O (40 mL) and brine solution (40mL) and then dried over MgSO4. It was then filtered, and the filtrate was concentrated under reduced pressure to leave the crude product, which was purified by column chromatography over silica gel (EtOAc-PE, 1:19) to give the olefin 1a as a colorless liquid. |
66% | To a suspension of methyltriphenylphosphonium bromide (1.87 g, 5.2 mmol) in dry THF (20 mL) was added 2 M standard solution of BuLi in THF (2.6 mL, 5.2 mmol). The mixture was stirred at room temperature for 1 h under argon atmosphere. A solution of Garner's aldehyde 10 (1 g, 4.4 mmol) in THF was added dropwise and the reaction mixture was allowed to stand at rt for 12 h. The solvent was evaporated to dryness, and the residue was dissolved in CH2Cl2, washed with brine (2 x 15 mL) and water (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (hexane - ethyl acetate v/v 20: 1) and 650 mg (66%) of a colorless oil was isolated. 1H and 13C NMR spectra were consistent with literature data [58]. IR (ATR, cm-1) nu: 2978, 1694, 1375, 1088; 1H NMR (400 MHz, CDCl3, rotamers) delta: 5.77 (m, 1H, =CH-), 5.11 (m, 2H, =CH2), 4.40 (br s, 0.4H, CH-N), 4.27 (br s, 0.6H, CH-N), 4.06 (dd, J = 8.8, 6.1 Hz, 1H, CH2-O), 3.75 (dd, J = 8.8, 2.3 Hz, 1H, CH2-O), 1.61 and 1.51 (2s, 6H, C(CH3)2), 1.43 (s, 9H, Boc); 13C NMR (100 MHz, CDCl3, minor rotamer marked with *) delta: 152.0, 137.4, 136.8*, 116.0*, 115.8, 93.9, 93.6*, 80.2*, 79.6, 68.1, 59.7, 28.4, 27.2*, 26.5, 24.8*, 23.7; HRMS (ESI): m/z calcd for C12H21NO3Na [M+Na]+: 250.1419, found: 250.1423. |
61% | To a slurry of MePPh3Br (Fluka Chemie GmbH; 3.74 g, 10.47 mmol) in 50 mL THF at - 78 C was added nBuLi solution, 2.5 M in hexanes (Aldrich; 3.84 ml, 9.60 mmol) dropwise via syringe. After 10 min, the reaction was warmed to RT, then recooled to 0 C. (S)-(-)-3-(tert-butoxycarbonyl)-(s)-4-formyl-2,2-dimethyl-l,3-oxazolidine (TCI America; 2.00 g, 8.72 mmol) (dissolved in 8 mL THF) was added dropwise via syringe. The reaction was stirred for several hours. The reaction was partitioned between saturated aqueous NH4C1 and Et20. The organic layer was washed with brine once and the organics were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The material was treated with DCM and adsorbed onto 15 g silica gel, dried, and purified by silica gel chromatography (120 g) using 0 - 30% EtOAc/hexane to give (R)-tert-butyl 2,2-dimethyl-4-vinyloxazolidine-3-carboxylate (1.21 g, 5.32 mmol, 61.0 % yield) as a clear/colorless oil: FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDCl3) delta ppm 5.69 - 5.96 (1 H, m), 5.06 - 5.27 (2 H, m), 4.20 - 4.47 (1 H, m), 4.05 (1 H, dd, J=8.8, 6.3 Hz), 3.76 (1 H, dd, J=8.8, 2.2 Hz), 1.37 - 1.71 (15 H, m). | |
Methyltriphenylphosphonium bromide (2.17 g, 6.07 mmol) was suspended inTHF (20 mL) at rt and 0.5 M KHMDS in toluene (11.66 mL, 5.83 mmol) was added. The resultant suspension was stirred at rt for Ih, then cooled to -78C and a solution of the aldehyde in THF (10 mL) was added drop-wise. The cooling bath was removed and the mixture was stirred for further 2 h. The reaction was quenched with MeOH (3 mL) and the resulting mixture poured into a mixture of sat. potassium sodium tatrate and water (1 : 1, 50 mL). Extraction with diethyl ether (2 x 25 mL), drying (MgSO4) and evaporation of the <n="122"/>solvent in vacuo gave a colourless oil which was purified by column chromatography on silica (ethyl acetate:hexanes = 1:9) to give the alkene ICEC0002 as a colourless oil (492 mg, 62%). [00240] [alpha]D (C 0.54, CHCl3) +11.1. 1H NMR (CDCl3, 300 MHz) delta 5.80 (m, IH), 5.19(m, 2H), 4.33 (m, IH), 4.05 (m, IH), 3.75 (m, IH), 1.61-1.44 (m. 15H). 13C NMR (CDCl3, 75 MHz) delta 162.3, 137.3, 136.7, 116.0, 115.8, 93.9, 68.0, 59.6, 28.4, 26.5, 23.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | 4-Formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (35c). A solution of dimethylsulfoxide (8.10 g, 103.71 mmol) in dichloromethane (10 ml) was added dropwise during 25 min to a solution of oxalyl chloride (6.58 g, 51.9 mmol) in dichloromethane (80 ml) at -78 0C. At the end of the addition the reaction solution was warmed up to -60 0C, and a solution of the alcohol 12b (8.0 g, 34.6 mmol) in dichloromethane (60 ml) was added dropwise during 50 min. N,N-diisopropylethyl amine (36 ml, 200 mmol) in dichloromethane (5 ml) was then added to the reaction mixture -45 0C during 30 min whereafter the reaction mixture was allowed to warm to 0 0C during 10 min. The reaction mixture was then transferred to a separation funnel charged with ice-cold 1 M HCl solution (130 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried and concentrated which gave the title compound (7.89 g, 99%). The residue was used in the next step without further purification. | |
99% | With chromium(VI) oxide; In dichloromethane; water; at 0 - 5℃; for 1h; | N - [(1,1-dimethylethoxy) carbonyl] -2,2-dimethyloxazolidinethanol138.7 g (0.6 M) was dissolved in 1,600 ml of methylene chloride Cool to 0-5 C.160 g (1.6 M) of chromium oxide (VI) was added to 2000 ml of purified waterAnd the solution is added dropwise to the solution over a period of 30 minutes.After the addition was completed, the mixture was further stirred at the same temperature for 30 minutes,Allow to stand for 30 minutes for layer separation.The first organic layer was collected and the aqueous layer was washed with 800 ml of methylene chlorideExtraction is carried out in the same manner as in the extraction.The first and second extraction organic layers were collected and washed with 500 ml of purified waterAfter layer separation, the organic layer was dried over MgSO 4, filtered and concentrated under reduced pressureThe methylene chloride organic layer was removed136 g (99%) of the title compound are obtained. |
99% | Step c; 4-Formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (12c); <n="58"/>A solution of dimethylsulfoxide (8.10 g, 103.71 mmol) in dichloromethane (10 ml) was added dropwise during 25 min to a solution of oxalyl chloride (6.58 g, 51.9 mmol) in dichloromethane (80 ml) at -78 0C. At the end of the addition the reaction solution was warmed up to -60 0C, and a solution of the alcohol 12b (8.0 g, 34.6 mmol) in dichloromethane (60 ml) was added dropwise during 50 min. N,N-diisopropylethyl amine (36 ml, 200 mmol) in dichloromethane (5 ml) was then added to the reaction mixture -45 0C during 30 min whereafter the reaction mixture was allowed to warm to 0 0C during 10 min. The reaction mixture was then transferred to a separation funnel charged with ice-cold 1 M HCl solution (130 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried and concentrated which gave the title compound (7.89 g, 99%). The residue was used in the next step without further purification. |
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 6h; | To a solution of (36) (80 mg, 0.346 mmol) stirring in CH2Cl2 (2 mL), under a nitrogen atmosphere, was added pyridinium chlorochromate (150 mg, 0.694 mmol). The reaction mixture was allowed to stir overnight then filtered through a plug of silica gel. The crude aldehyde was carried on to the following step |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.24 g | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere; | Example 14 Synthesis of tert-Butyl (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate (14*) To a solution of Weinreb amide 13* (8.00 g, 27.7 mmol) in THF (100 mL) at 0C were added LiAlH4 (1.0 M in THF, 13.9 mL, 13.9 mmol) dropwise and the solution was stirred for 1 h at 0 C. After 1 h, the solution was cooled to -10 C and KHSO4 (1M, 70 mL) was added carefully and the solution was diluted with Et2O (170 mL). The mixture was allowed to warm to r.t. and stirred for 30 min. The organic layer was separated, dried over MgSO4, filtered and the solvent was removed in vacuo to yield Garner's aldehyde 14* as a pale yellow oil (6.24 g, > 95% purity by 1H NMR). The NMR spectra consist of two sets of signals due to the presence of rotamers. 1H NMR (250 MHz, CDCl3) delta 9.58 (d, J = 0.8 Hz, 1 H), 9.52 (d, J = 2.5 Hz, 1 H), 4.32 (m, 1 H), 4.16 (m, 1 H), 4.06 (m, 4 H), 1.53-1.63 (m, 12 H), 1.49 (s, 9 H), 1.40 (s, 9 H). All spectral data in good accordance with reported data (Synthesis 1998, 1707). The crude product was used in the subsequent reaction without further purification. |
6.24 g | Example B.2: Synthesis of tert-Butyl (S)-4-formyl-2,2-dimethyloxazolidine-3- carboxylate (14*)To a solution of Weinreb amide 13* (8.00 g, 27.7 mmol) in THF (100 mL) at 0 C were added LiAIH4 (1 .0 M in THF, 13.9 mL, 13.9 mmol) dropwise and the solution was stirred for 1 h at 0 C. After 1 h, the solution was cooled to -10 C and KHSO4 (1 M, 70 mL) was added carefully and the solution was diluted with Et2O (170 mL). The mixture was allowed to warm to r.t. and stirred for 30 min. The organic layer was separated, dried over MgSO4, filtered and the solvent was removed in vacuo to yield Garner's aldehyde 14* as a pale yellow oil (6.24 g, > 95% purity by 1H NMR). The NMR spectra consist of two sets of signals due to the presence of rotamers. 1H NMR (250 MHz, CDCI3) delta 9.58 (d, J = 0.8 Hz, 1 H), 9.52 (d, J = 2.5 Hz, 1 H), 4.32 (m, 1 H), 4.16 (m, 1 H), 4.06 (m, 4 H), 1 .53-1 .63 (m, 12 H), 1 .49 (s, 9 H), 1 .40 (s, 9 H). Allspectral data in good accordance with reported data (Synthesis 1998, 1707). The crude product was used in the subsequent reaction without further purification | |
With potassium hydrogensulfate; lithium aluminium tetrahydride; In tetrahydrofuran; | tert-Butyl (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate (4) To a solution of Weinreb amide 3 (8.00 g, 27.7 mmol) in THF (100 mL) at 0 C were added LiAlH4 (1.0 M in THF, 13.9 mL, 13.9 mmol) dropwise and the solution was stirred for 1 h at 0 C. After 1 h, the solution was cooled to -10 C and KHSO4 (1 M, 70 mL) was added carefully and the solution was diluted with Et2O (170 mL). The mixture was allowed to warm to r.t. and stirred for 30 min. The organic layer was separated, dried over MgSO4, filtered and the solvent was removed in vacuo to yield Garner's aldehyde 4 as a pale yellow oil (6.24 g, > 95% purity by 1H NMR). The NMR spectra consist of two sets of signals due to the presence of rotamers. 1H NMR (250 MHz, CDCl3) delta 9.58 (d, J = 0.8 Hz, 1 H), 9.52 (d, J = 2.5 Hz, 1 H), 4.32 (m, 1 H), 4.16 (m, 1 H), 4.06 (m, 4 H), 1.53-1.63 (m, 12 H), 1.49 (s, 9 H), 1.40 (s, 9 H). The crude product was used in the subsequent reaction without further purification. |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1h; | 10229] To a solution of Weinreb amide 3 (8.00 g, 27.7 mmol) in THF (100 mE) at 0 C. were added EiA1H4 (1.0 M in THF, 13.9 mE, 13.9 mmol) dropwise and the solution was stirred for 1 h at 0 C. After 1 h, the solution was cooled to-10C. and KHSO4 (1M, 70 mE) was added careffilly and the solution was diluted with Et20 (170 mE). The mixture was allowed to warm to r.t. and stirred for 30 mm. The organic layer was separated, dried over MgSO4, filtered and the solvent was removed in vacuo to yield Gamer?s aldehyde 4 as a pale yellow oil (6.24 g, >95% purity by ?H NMR). The NMR spectra consist of two sets of signals due to the presence of rotamers. ?H NMR (250 MHz, CDC13) oe 9.58 (d, J=0.8 Hz, 1H), 9.52 (d, J=2.5 Hz, 1H), 4.32 (m, 1H), 4.16 (m, 1H), 4.06 (m, 4H), 1.53-1.63 (m, 12H), 1.49 (s, 9H), 1.40 (s, 9H). The crude product was used in the subsequent reaction without thrther purification | |
(R)-terr-butyl 2,2-dimethyl-4-vinyloxazolidine-3-carboxylate (ICEC0002)[00238] The hydroxamate ICECOOOl (1 g, 3.47 mmol) was dissolved in anhyd. THF(15 mL) and cooled to 00C. 1.0 M LiAlH4 in THF (0.87 mL, 1.73 mmol) was added drop-wise and the mixture was stirred for 30 min. The reaction was then cooled further to -15C and sat. aq. KHSO4 (10 mL) was added carefully, the solution diluted with diethyl ether (25 mL) and stirred vigorously for 30 min. The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to give the corresponding aldehyde as a pale yellow oil, which was directly used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In benzene at 20℃; for 0.5h; | |
94% | In benzene at 20℃; | To a stirred solution of tert-butyl (S)-4-formyl-2,2-dimethyloxazolidine-3- carboxylate (1.5 g, 6.54 mmol) in dry benzene (150 mL) at 23°C, ethyl 2-(triphenyl-15- phosphaneylidene)acetate (C-2 Wittig ylide) (2.74 g, 7.85 mmol) was added to the reaction mixture and stirred for 7 h. The reaction was monitored by TLC, after completion of reaction precipitate was filtered over vaccuum. The organic layer was concentrated under vacuum and purified by flash column chromatography to give tert-butyl (/?, £)-4-(3 -ethoxy-3 -oxoprop-1- en-l-yl)-2,2-dimethyloxazolidine-3-carboxylate (1.84 g, 94 %) as a colorless oil. |
92% | In benzene Heating; |
90% | In tetrahydrofuran at 60℃; for 5h; Inert atmosphere; | |
90% | In benzene at 20℃; for 4h; | |
87% | In tetrahydrofuran for 2h; Heating; | |
82% | In benzene for 36h; Ambient temperature; | |
10.7 g | In benzene at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | This product was synthesized using the conditions described by Meffre et al.4To a solution of (S)-5 (4.43 g, 19.3 mmol) in 40 mL of methanol at -12C (salt/ice/water bath)was added a solution of 6 (5.55 g, 28.9 mmol) in 40 mL of methanol. The reaction mixturewas stirred at -12C during 15min, solid potassium carbonate (5.33 g, 38.6 mmol) was addedin three equal portions in 30 min and the ice bath is removed. The reaction was stirred at roomtemperature during 2.5h and 110 mL of saturated aqueous ammonium chloride solution wasadded. The aqueous phase was extracted with petroleum ether (3*120 mL). The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/PE,0/100 ramping to 100/0, v/v) to give compound (R)-4 (3.36 g, 1.33 mmol) in 77% as a clearoil; Rf 0.78 (EtOAc/PE: 20/80; v/v). 1H NMR (300 MHz, CDCl3) delta: 1.49, 1.63 (2s, 15H,C(CH3)3, C(CH3)2), 2.27 (br s, 1H, C?C-H), 3.99-4.07 (m, 2H, CH2), 4.50-4.61 (m, 1H, CH).13C NMR (75 MHz, CDCl3) delta: 24.5, 25.3, 26.0, 27.0, 28.5 (5s, C(CH3)2, C(CH3)3), 48.5(CH), 68.8 (CH2), 70.2, 70.6 (C?C-H), 80.5, 81.0 (C(CH3)3), 82.5, 82.9 (C?C-H), 94.2, 94.6(C(CH3)2), 151.5, 151.8 (NCO2). [alpha]D20 = -95.2 (c 1.24, CHCl3) ; litt4. [alpha]D20= -96.5 (c 1.23,CHCl3). HRMS (ES+) [M+Na]+ calcd for C12H19NO3Na, 248.1263; found, 248.1264. IR (cm-1): 3270, 1697. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 0 - 20℃; for 66h; | Intermediate 7a(S)-tert-butyl 2,2-dimethyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazolidine-3-carboxylate To a mixture of (S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g, 4.36 mmol), (trifluoromethyl)trimethylsilane (2.0 M solution in THF, 2.6 mL, 5.20 mmol) in THF (10 mL) was added tetrabutylammonium fluoride (1.0 M solution in THF, 0.1 mL, 0.10 mmol) at 0 C. After addition, the mixture was stirred at room temperature for 60 h. Then, tetrabutylammonium fluoride (1.0 M solution in THF, 9 mL, 9.0 mmol) was added and the mixture stirred for another 6 h and subsequently quenched by adding saturated aq. NaHCO3 solution, extracted with EtOAc. The extracts were washed with saturated aq. NaHCO3 solution, water, brine and dried over Na2SO4. Concentration and purification gave (S)-tert-butyl 2,2-dimethyl-4-(2,2,2-trifluoro-1-hydroxyethyl)oxazolidine-3-carboxylate (1.21 g, 92%), which showed a complicated NMR spectrum because of the different comformers. |
1.42 g | With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃;Inert atmosphere; | (Trifluoromethyl)trimethylsilane (0.82 mL, 0.96 g/mL, 5.6 mmol) was added to a solution of tert-butyl (4 S)-4-formyl-2,2-dimethyl-oxazolidine-3 -carboxylate (1 .06 g, 4.62 mmol) and TBAF (0.11 mL, 1 M in THF, 0.11 mmol) in THF (28 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred overnight atroom temperature. Tetrabutylammonium fluoride (9.25 mL, 1 M, 9.25 mmol) was added to the reaction mixture and stirring was continued overnight. The reaction mixture was quenched with NaHCO3 (aq. sat.), and extracted with EtOAc (3 times). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (heptane/ethyl acetate100/0 to 0/100) to afford tert-butyl (4S)-2,2-dimethyl-4-(2,2,2-trifluoro- 1 -hydroxyethyl)oxazolidine-3-carboxylate (1.42 g) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With Wilkinson's catalyst; triphenylphosphine; isopropyl alcohol In tetrahydrofuran at 25℃; for 4h; | |
80% | With (iPr)CuCl; triphenylphosphine; isopropyl alcohol In tetrahydrofuran; diethyl ether at 60℃; for 3h; | |
With triphenylphosphine In tetrahydrofuran; isopropyl alcohol at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: dodecyltriphenylphosphonium bromide With potassium hexamethylsilazane In tetrahydrofuran; toluene at -78 - 20℃; for 0.5h; Stage #2: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester In tetrahydrofuran; toluene at -78℃; Stage #3: With methanol In tetrahydrofuran; toluene at -78℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 60% 2: 3% | Stage #1: hexyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; Stage #2: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester In tetrahydrofuran; hexane at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Under argon atmosphere, to a solution of pentadecyne (2.47 g, 11.8 mmol) in dry THF (107 mL) at -20 C, was added n-butyllithium (2.5 M in hexanes, 5.33 mL, 13.3 mmol). The resulting mixture was stirred at -20 C for 45 min before a solution of Garner aldehyde (2.01 g, 8.8 mmol) in dry THF (57 mL) was added dropwise via syringe. The reaction mixture was stirred at -20 C for 90 min then quenched with saturated NH4Cl aqueous solution (60 mL) and diluted with H2O (40 mL). The aqueous phase was extracted with EtOAc, the combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude oil, which was purified by flash chromatography on silica (10/1 Hex/EtOAc). The product was obtained as a colourless oil and TLC showed only the major erythro stereoisomer (2.48 g, 65%).Rf: [4/1 Hex/EtOAc]: 0.43?H (500 MHz, CDCl3, 303 K): 0.86 (3H, t J=7.2 Hz); 1.24 (20H, wide s); 1.33 (1H, m); 1.42-1.64 (15H, m); 2.18 (2H, td J=7.2, 1.7 Hz); 3.89 (1H, br s); 4.01-4.12 (2H, m); 4.50 (1H, br d J=6.7 Hz); 4.70 (1H, br d J=6.9 Hz).?c (125 MHz, CDCl3, 303 K): 14.1; 18.7; 22.6; 25.7; 28.3; 28.5-29.6; 31.9; 62.8; 64.1; 65.1; 77.8; 81.2; 86.6; 94.9; 154.1.m/z (ESI Pos): 460.4 [M+Na] 100%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: hexyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃; Stage #2: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester In tetrahydrofuran; hexane at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of (S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (4.86 g, 21.2 mmol) in dichloromethane (100 mL) is stirred at room temperature and then <strong>[79265-30-8]2-(trimethylsilyl)thiazole</strong> (5.0 g, 31.8 mmol) in dichloromethane (30 mL) is added dropwise over 30 minutes. The resulting mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the mixture is then treated with 1N tetrabutylammonium fluoride in THF (31.8 mL, 31.8 mmol). The resulting mixture is stirred at room temperature for 1 hour and then the solvent is removed under reduced pressure. Saturated NaHCO3 solution is added and the resulting mixture is extracted with EtOAc. The organic extracts are dried (Na2SO4) and then concentrated to an oil under reduced pressure. The product is purified by chromatography on silica gel using 8/2 hexane/EtOAc to provide the desired product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; at 0 - 20℃; for 18h; | A 3-necked, 1000 mL round-bottom flask fitted with a N2 inlet adapter, magnetic stir bar, drying tube, temperature guage, and a septa was charged with methyl (S)- (-)-3- (TERT-BUTOXYCARBONYL)-2, 2-DIMETHYL-4-OXAZOLIDINE-CARBOXYLATE (15. 42 g, 59.46 mmole) and 120 ML of anhydrous toluene. The solution was cooled TO-78 C in A dry ice/acetone bath. A solution of DIISOBUTYLALUMINUM hydride in toluene (69.5 ML, 104.1 mmole) was cooled TO-78 C in A separate dry ice/acetone bath and added to the ester solution under N2 pressure via a steel cannula over a period of 30 min. The rate of addition was adjusted to prevent the reaction mixture from warming above- 70 C. After addition was complete, the mixture was stirred at-78 C for an additional 30 minutes. Excess hydride was quenched by the dropwise addition of 20 mL of pre-chilled (-78 C) methanol, again keeping the reaction temperature below- 70 C. The resulting white slurry was poured into 500 mL of ice-cold 1 N HC1. The aqueous layer was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with 300 mL 1 N HC1, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield (S)-4- formyl-2,2-dimethyl-3-oxazolidinecarboxylic acid tert-butyl ester (14.65 g) as a yellow oil. The residue was dissolved in 200 mL of anhydrous methanol, and the flask was flushed with N2. <strong>[6436-90-4]N-Benzylglycine ethyl ester</strong> (23.0 g, 118. 9 mmole) and acetic acid (6. 8 mL, 118. 9 mmole) were added, and the reaction mixture was cooled in an ice bath. A solution of sodium cyanoborohydride in tetrahydrofuran (100 mL, 100 mmole) was added via a cannula under positive N2 pressure. The reaction mixture was stirred at room temperature for 18h. A large excess of solid K2C03 was added until gas evolution ceased. The slurry was concentrated almost to dryness under reduced pressure and the residue was dissolved in 300 mL of dichloromethane. The organic layer was washed with 300 mL of 1: 1: 1 water/saturated NAHC03/BRINE. The aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, gradient: 15% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave 16.83 g (70%) of (S)-4-[(BENZYLETHOXYCARBONYL-METHYLAMINO)- methyl] -2, 2-dimethyl-3-oxazolidinecarboxylic acid tert-butyl ester as a clear viscous oil. MS : 407. 3 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at 60℃; for 1h; Stage #2: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester In tetrahydrofuran; hexane at -78℃; for 12h; | 46 Example 46; tert-butyl-(4R)-2,2-dimethyl-4-vinyl-1,3-oxazolidine-3-carboxylate; Methyltriphenylphosphonium bromide (3.000 g, 8.6 mmol) was suspended in THF (30 ml) under N2 at room temperature, and nBuLi (2.5 M in hexanes) (3 ml, 1.8 eq.) was added. The resulting yellow suspension was heated to 60° C. and stirred for 1 hour. After an hour the mixture was cooled to -78° C. and a cold (-78° C.) solution of Garner's aldehyde (0.962 g, 4.2 mmol) in anhydrous THF (7.3 ml) was added dropwise. The solution was then allowed to stir for 12 hours and monitored by t.l.c. (diethyl ether:hexane, 1:4), before quenching with methanol (10 ml). The resulting mixture was poured into a solution of saturated potassium sodium tartrate and water (1:1, 120 ml), and then concentrated under reduced pressure to remove the TIF and methanol, before extracting with ether. The organic phase was then dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (diethyl ether:hexane, 1:4) afforded the olefin product (0.766 g, 81%). MS(CI)+ m/z: calculated mass for C12H21NO3 is 227.30, found 227.1917 ([M+]); IR (film) νmax (cm-1) 1700, 1385; 1H NMR (CDCl3, 400 Mhz), δ=5.82 (m, 1H, H6), 5.17 (m, 2H, H7,7'), 4.35 (m, 1H, H4), 4.04 (dd, J=8.8, 6.1 Hz, 1H, H5), 3.74 (ddd, J=8.8, 6.6, 2.3 Hz, 1H, H5'), 1.60 and 1.51 (2s, 6H, -OC(CH3)2N-), 1.44 (s, 9H, COOC(CH3)3); 13C-NMR (CDCl3, 100.6 MHz) δ=152.0 (-NCOO-), 137.4 (CH, C6), 115.7 (CH2, C7), 94.0 (-OC(CH3)2N-), 79.6 (OC(CH3)3), 68.1 (CH2, C5), 60.0 (CH, C4), 28.4 (CH3, OC(CH3)3), 26.5 and 23.7 (CH3, -OC(CH3)2N-); [α]D=+14.5° (lit.- T. Moriwake, S.-I. Hamano, S. Saito, S. Torii, Chem. Lett., 1987, 2085. +15°) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester; diazomethyl-trimethyl-silane With triphenylphosphine; isopropyl alcohol; copper(l) chloride In tetrahydrofuran at 60℃; Stage #2: With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran; toluene at 80℃; Stage #3: 2-methyl-1-propenylbromide With sodium hydroxide In tetrahydrofuran; toluene at 90℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.5% | Stage #1: 1-bromo-4-(tert-butyl)cyclohex-1-ene With N,N,N,N,-tetramethylethylenediamine; tert.-butyl lithium In tetrahydrofuran; pentane at -78℃; for 0.1h; Stage #2: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester In tetrahydrofuran; pentane at -78℃; for 1h; | Synthesis of (S)-terf-butyl 4-((R)-(4-tert-butylcyclohex-1-enyl)(hydroxy)methyl)-2,2- dimethyloxazolidine-3-carboxylate; To a stirred solution of 300 mg (1 .39 mmol) 1 -bromo-4-ferf-butylcyclohex-1-ene in 5 ml THF at -78 °C 0.80 ml (1.39 mmol) t-BuLi-Solution (1 .7 M in pentane) were added drop wise. After 3 min 100 μΙ TMEDA were added. Stirring was continued for 3 min at -78 °C. A solution of 318 mg (1.39 mmol) Garneraldehyde in 5 ml THF was added drop wise and stirring was continued for 1 h. The mixture was poured in 10 ml ice cooled water and extracted with three times with 10 ml Ethyl acetate. Combined organic layer was washed with 20 ml saturated NaCI-Solution and dried over Na2S04. Solvent was removed to give 400 mg slightly yellow oil as crude product, which was purified by chromatography on silica gel eluted withcyclohexane/ethyl acetate 9:1 -4:1 . Yield: 196 mg (0.534 mmol, 38.5 % d. Th.) colorless liquid, C2iH37N04 (367.5 g/mol).Rf (cyclohexane /ethyl acetate 7:3) = 0.501H-NMR (CDCI3; 500 MHz): δ = 0.85 (d, J =1 .6 Hz, 9H), 1 .42-1.43 (m, 2H), 1.48 (s, 6H), 1.50 (s, 9H), 1.71 -1 .97 (m, 3H), 1 .96-2.10 (m, 2H), 3.76 (dd, J =9.1 Hz, J2=9.1 Hz, 1 H), 3.84 (dd, Ji=5.8 Hz, J2=8.0 Hz, 1 H), 4.02 (dd, Ji=9.9 Hz, J2=9.9 Hz, 1 H), 4.09 (br, 1 H), 5.70 (m, 1 H) ppm.13C-NMR (CDCI3; 125 MHz): δ = 14.2, 21 .1 , 23.9, 24.8, 26.7, 26.8, 27.2, 28.3, 28.4, 32.1 , 32.3, 44.5, 60.4, 66.5, 80.2, 95.0, 1 19.0, 126.6, 171.6 ppm.HR-MS p ESI calculated for C2iH37N04+H+ m/z = 368.2796, found: 368.2795.HR-MS p ESI calculated for C2iH37N04+Na+ m/z = 390.2616, found: 390.2615. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56%; 20% | With methyllithium; In tetrahydrofuran; at -78℃; for 2h; | To a solution of 4 (0.509g, 2.46mmol) and (S)-Garner's aldehyde (16, 1.35g, 5.90mmol) in THF (9.8mL) was added 1.06M MeLi/LiBr-free ether solution (5.57mL, 5.90mmol) dropwise at -78C. The resulting mixture was stirred at the same temperature for 2h, and then quenched with NH4Cl aq. The reaction mixture was extracted with Et2O three times. The combined extracts were dried over anhydrous Na2SO4, and the solvents were removed under reduced pressure. The residue was chromatographed on a silica gel to give the corresponding alcohol 17a (0.49g, 1.38mmol, 56% yield, anti isomer) and 17b (0.18g, 0.49mmol, 20% yield, syn isomer) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80 % de | With magnesium In tetrahydrofuran at -78 - 20℃; for 1h; Overall yield = 86 %; | 2.2 tert-Butyl (S)-4-((S)-1-hydroxyhexadecyl)-2,2-dimethyloxa zolidine-3-carboxylate (10) To the solution of Garner aldehyde (9) (2.0 g, 8.72 mmol)in THF (10 mL), was added at -78 °C pentadecyl magnesiumbromide in THF (10 mL) which was preparedfrom 1-bromopentadecane (7.58 mL, 26.16 mmol) andMg (0.847 g, 34.88 mmol) in the usual manner. Themixture was stirred at the same temperature (-78 °C)for 1 hour and then gradually brought to r.t. The mixturewas then stirred overnight at r.t. to produce themixture of diastereomers 10 and 10a. The reaction wasquenched by the addition of aqueous saturated NH4Cl(10 mL) and extracted with AcOEt. The organic layerwas washed with 5% aqueous HCl (10 mL), water,brine and then dried over Na2SO4. The two diastereomers10 and 10a were separated by careful CC (silicagel, 100-200 mesh, 0-5% increasing amount ofAcOEt in hexane) to produce two diastereomeric alcohols10 and 10a in the ratio 9:1 (syn:anti, 9:1) with86% yield. The pure alcohol 10 (2.98 g) was obtainedas a colorless oil. [α]25D= -32.2 (c =2.0, CHCl3). IR max (KBr)/cm-1: 3440, 2925, 2855, 1701, 1366, 1258,1175, 1061. 1H NMR (500 MHz, CDCl3): 4.10-3.49 (m, 4H); 1.62-1.55 (m, 2H); 1.49 (s, 12H); 1.45 (s, 3H);1.25 (br. s, 26H); 0.88 (t , J = 6.8 Hz, 3H). 13C NMR(125 MHz, CDCl3): 154.1; 94.2; 81.0; 72.9; 64.7; 62.3;34.4; 32.7; 31.8; 29.6; 29.6; 29.5; 28.3; 26.4; 26.0; 24.2;22.6; 14.0. ESIMS: m/z 442 [M+H]+. Anal Calcd. forC26H51NO4: C, 70.70; H, 11.64%. Found: C, 70.60; H,11.68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 3h; | Step 1 : tert-butyl (R)-4-(((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)methyl)-2,2- dimethyloxazolidine-3-carboxylate [00225] To a solution of Garner's aldehyde (0.458 g, 2.0 mmol) in 1,2-dichloroethane (20 mL) was added tert-butyl (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate (0.365 g, 2.09 mmol). After stirring at room temperature for 5 min, NaBH(OAc)3 (0.43 g, 2.03 mmol) was added in portions. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHC03 (25 mL) was added, the organic phase was separated, and the aqueous phase was further extracted with CH2CI2 (25 mL). The combined organic layers were washed with saturated NaHC03 (20 mL) and brine (20 mL), then dried (MgS04) and concentrated in vacuo to give a colorless oil. Purification by silica gel column chromatography with 1% and 5% CH30H/CH2C12 yielded tert-butyl (R)-4-(((2-((ferf- butoxycarbonyl)amino)ethyl)(methyl)amino)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.684 g, 88%) as a colorless oil. 1H MR (300 MHz, CDC13) delta 5.03, 4.86 (br, 1H), 4.0-3.83 (br, 1H), 3.94 (s, 2H), 3.18 (br, 2H), 2.6-2.4 (m, 4H), 2.28 (d, 3H, J = 6.9 Hz), 1.6-1.4 (m, 24H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Compound 3 (12.2 g, 29.9 mmol) was dissolved in dry tetrahydrofuran (THF) (150 mL) under a nitrogen atmosphere, and n-butyllithium (2 M in THF, 22.5 mL, 44.9 mmol) was slowly added dropwise at -78 C. The mixture was stirred at -78 C for 30 min; the cooling bath was removed, and the mixture was further stirred for 1 h. Then, Garner?s aldehyde (6.88 g, 29.9 mmol) was dissolved in dry THF (20 mL) at -78 C and added dropwise. After stirring for 30 min at the same temperature, the cooling bath was removed. After confirming that the reaction was completed after 2.5 h, the reaction was quenched by addition of a saturated aqueous NH4Cl solution. Ethyl acetate (200 mL) was added to the reaction solution and partitioned. The separated organic layer was dried over anhydrous Na2SO4 and concentrated using a rotary evaporator. The resulting oil was purified by silica column chromatography (EA:Hex = 1:4, Rf = 0.34) to obtain compound 4 (Colorless oil, 17.5 g, 92 1H NMR (400 MHz, CDCl3) delta 7.70 (m, 4H), 7.42 (m, 6H), 4.74 (br, 1H), 4.54 (br, 1H), 4.09 (m, 2H), 3.94 (br, 1H), 3.67 (t, J = 6.4 Hz), 2.21 (td, J = 6.4, 1.6 Hz), 1.61 (m, 5H), 1.52 (s, 13H), 1.37 (m, 5H), 1.27 (s, 6H), 1.07 (s, 9H). 13C NMR (100 MHz, CDCl3) delta 151.1, 135.5, 134.2, 129.6, 127.7, 95.0, 86.8, 81.3, 77.9, 65.2, 64.3, 64.1, 62.8, 32.6, 29.5, 29.4, 29.1, 28.9, 28.6, 28.4, 28.2, 26.9, 25.8, 19.2, 18.8. | |
52% | Compound 4 (12.2 g, 29.99 mmol) was dissolved in dry tetrahydrofuran (THF) (300 ml) under an Ar atmosphere,Add n-butyllithium (22.5 ml, 44.9 mmol; 2M in hexane) slowly at -70 C.Stir at the same temperature for 30 minutes, remove the cooling bath and stir for 60 minutes.Again, below -70 C,Garner's aldehyde (6.88 g, 29.9 mmol) is dissolved in dry THF (20 ml) and added dropwise. Stir at the same temperature for 30 minutes and remove the cooling bath. After 2.5 hours, a saturated aqueous NH4Cl solution is added to terminate the reaction. Extract with DCM (200 ml X2). The organic layer was dried over Na2SO4, filtered and concentrated. The concentrate was separated and purified by column chromatography to obtain Compound 5 (9.9 g, 52%) (FIG. 4). | |
52% | Compound 4 (12.2 g, 29.99 mmol) was added under Ar atmosphere.Dry tetrahydrofuran (THF) (300 ml) and slowly add dropwise n-butyllithium (22.5 ml, 44.9 mmol; 2M in hexane) at -70 C.Stir at the same temperature for 30 minutes, remove the cooling bath and stir for 60 minutes.Again below -70 C, Garner's aldehyde (6.88 g, 29.9 mmol) is added dropwise in dry THF (20 ml).Stir at the same temperature for 30 minutes and remove the cooling bath. After 2.5 hours, the reaction is terminated by addition of a saturated aqueous NH 4 Cl solution.Extract with DCM (200 ml X 2). The organic layer was dried over Na 2 SO 4, filtered and concentrated. The concentrate was separated and purified by column chromatography to give compound 5 (9.9 g, 52%) (Fig. 4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran | ||
With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran |
Tags: 102308-32-7 synthesis path| 102308-32-7 SDS| 102308-32-7 COA| 102308-32-7 purity| 102308-32-7 application| 102308-32-7 NMR| 102308-32-7 COA| 102308-32-7 structure
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