2-O-tert-butyl 1-O-methyl oxalate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl chlorooxoacetate in TBME (1 mmol/ml) was added at 0-5° C. tert-butanol (1.5 equiv.), followed by dropwise addition of pyridine (1.5 equiv.). The resulting mixture was stirred at room temperature for 20 h. Water (15 vol.) was added, the mixture was extracted with TBME twice. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give a colorless oil. the mixture was extracted with TBME twice The combined organic extracts were washed with brine dried over anhydrous Na2SO4 concentrated under vacuum to give a colorless oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl chlorooxoacetate in TBME (1 mmol/ml) was added at 0-5° C. tert-butanol (1.5 equiv.), followed by dropwise addition of pyridine (1.5 equiv.). The resulting mixture was stirred at room temperature for 20 h. Water (15 vol.) was added, the mixture was extracted with TBME twice. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give a colorless oil. the mixture was extracted with TBME twice The combined organic extracts were washed with brine dried over anhydrous Na2SO4 concentrated under vacuum to give a colorless oil

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium diisopropylamide was generated by addition of n-butyl lithium (17 mL, 1.9M in hexane, 33.33 mmol), di-isopropyl amine (4.66 mL, 33.33 mmol) in tetrahydrofuran (15 mL) at 0° C. and stirred for 10 min. In a separate flask, a mixture of benzyloxy-acetic acid methyl ester (3) (4 g, 22.22 mmol) and oxalic acid tert-butyl ester methyl ester (2) (5.33 g, 33.33 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. and then lithium diisopropylamide was added at −78° C. The mixture was stirred at −78° C. for 1 h. After 1 h, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for another 1 h. After completion of the reaction, the reaction was quenched with 1N HCl, and extracted with ethyl acetate. The separated organic part was dried over sodium sulfate and concentrated under reduced pressure, passed over a normal silica column using 25% ethyl acetate in hexane to get (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (2.4 g, 35%) as ketoenol tautomers and ketone hydrate as a thick light yellow coloured oil. These were immediately used for next step. The mixture was stirred at −78° C. for 1 h After 1 h to warm to room temperature stirred at room temperature for another 1 h After completion of the reaction the reaction was quenched with 1N HCl extracted with ethyl acetate The separated organic part was dried over sodium sulfate concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl methyl oxalate (5.8 g, 36 mmol) and methyl 2-(benzyloxy)acetate (6.5 g, 36 mmol) in THF (80 mL) at −78° C. was added a dropwise a solution of LDA (prepared by dropwise addition of nBuLi (20 mL, 50 mmol) to diisopropylamine (7.1 mL, 50 mmol) in THF (20 mL) at 0° C. then stirring for 10 min. After the addition, the reaction mixture was stirred at −78° C. for 2 h then allowed to warm to rt over the course of 1 h. The reaction mixture was cooled to 0° C. then cold 1 N HCl (ca. 70 mL) was added. The resulting solution was extracted with EtOAc (3×), and the combined organic portions dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to give 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (5.4 g, 49% yield) as tan viscous oil. O-Methylisourea hydrogensulfate (2.5 g, 14 mmol) and 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (5.4 g, 17 mmol) were stirred in anhydrous MeOH (15 mL) at 0° C. under argon. Sodium methoxide (10 g, 46 mmol) in MeOH (25% wt) was added and the reaction mixture was stirred at room temperature for 40 h. MeOH (3 mL) was added and the mixture cooled in an ice bath. 1 N HCl (11 mL) was added to acidify the mixture and the resulting precipitate was collected and rinsed with cold H2O:MeOH (10:1). The filtrate was concentrated under reduced pressure and the residue was extracted with CH2Cl2 (2×). The organic extracts and the precipitate were combined, concentrated under reduced pressure, then purified by silica gel chromatography eluting with EtOAc/hexanes to give Compound 46d (2.8 g, 58% yield) as a white solid. LCMS ESI 333.2 (M+H-tBu), RT=2.02 min (Method Q). 1H NMR (400 MHz, DMSO-d6) δ 13.48-12.16 (m, 1H), 7.91-6.79 (m, 5H), 5.02 (s, 2H), 3.86 (s, 3H), 1.44 (s, 9H). After the addition the reaction mixture was stirred at −78° C. for 2 h The reaction mixture was cooled to 0° C. The resulting solution was extracted with EtOAc (3×) the combined organic portions dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with EtOAc/hexanes

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl methyl oxalate (34 g, 210 mmol) and methyl (benzyloxy)acetate (35 g, 190 mmol) were dissolved in tetrahydrofuran (250 mL) and a solution of LDA in tetrahydrofuran prepared at −78° C. was added dropwise under a nitrogen atmosphere, followed by stirring at the same temperature for 3 hours. The temperature of the reaction solution was gradually raised to −40° C., and subsequently hydrochloric acid (2 M, 210 mL) was added, followed by extraction with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to afford 4-tert-butyl 1-methyl 2-(benzyloxy)-3-oxosuccinate (62 g) as a yellow oil. was added dropwise under a nitrogen atmosphere followed by extraction with ethyl acetate The extract was washed with water by drying over anhydrous magnesium sulfate the solvent was distilled off under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl chlorooxoacetate in TBME (1 mmol/ml) was added at 0-5° C. tert-butanol (1.5 equiv.), followed by dropwise addition of pyridine (1.5 equiv.). The resulting mixture was stirred at room temperature for 20 h. Water (15 vol.) was added, the mixture was extracted with TBME twice. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give a colorless oil. the mixture was extracted with TBME twice The combined organic extracts were washed with brine dried over anhydrous Na2SO4 concentrated under vacuum to give a colorless oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl methyl oxalate (5.8 g, 36 mmol) and methyl 2-(benzyloxy)acetate (6.5 g, 36 mmol) in THF (80 mL) at −78° C. was added a dropwise a solution of LDA (prepared by dropwise addition of nBuLi (20 mL, 50 mmol) to diisopropylamine (7.1 mL, 50 mmol) in THF (20 mL) at 0° C. then stirring for 10 min). After the addition, the reaction mixture was stirred at −78° C. for 2 h then allowed to warm to rt over the course of 1 h. The reaction mixture was cooled to 0° C. then cold 1 N HCl (ca. 70 mL) was added. The resulting solution was extracted with EtOAc (3×), and the combined organic portions dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to give 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (5.4 g, 49% yield) as tan viscous oil. O-Methylisourea hydrogensulfate (2.5 g, 14 mmol) and 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (5.4 g, 17 mmol) were stirred in anhydrous MeOH (15 mL) at 0° C. under argon. Sodium methoxide (10 g, 46 mmol) in MeOH (25% wt) was added and the reaction mixture was stirred at rt for 40 h. MeOH (3 mL) was added and the mixture cooled in an ice bath. 1 N HCl (11 mL) was added to acidify the mixture and the resulting precipitate was collected and rinsed with cold H2O:MeOH (10:1). The filtrate was concentrated under reduced pressure and the residue was extracted with CH2Cl2 (2×). The organic extracts and the precipitate were combined, concentrated under reduced pressure, then purified by silica gel chromatography eluting with EtOAc/hexanes to give Compound 43c (2.8 g, 58% yield) as a white solid. LCMS=2.02 min using analytical method (Q), 333.2 (M+H-tBu). 1H NMR (400 MHz, DMSO-d6) δ 13.48-12.16 (m, 1H), 7.91-6.79 (m, 5H), 5.02 (s, 2H), 3.86 (s, 3H), 1.44 (s, 9H). After the addition the reaction mixture was stirred at −78° C. for 2 h The reaction mixture was cooled to 0° C. The resulting solution was extracted with EtOAc (3×) the combined organic portions dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with EtOAc/hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl chlorooxoacetate in TBME (1 mmol/ml) was added at 0-5° C. tert-butanol (1.5 equiv.), followed by dropwise addition of pyridine (1.5 equiv.). The resulting mixture was stirred at room temperature for 20 h. Water (15 vol.) was added, the mixture was extracted with TBME twice. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give a colorless oil. the mixture was extracted with TBME twice The combined organic extracts were washed with brine dried over anhydrous Na2SO4 concentrated under vacuum to give a colorless oil