methyl 3-oxocyclobutane-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a suspension of sodium hydride (0.27 g, 6.63 mmol, 60% oil dispersion) in dry tetrahydrofuran (10 ml), was added dropwise with vigorous stirring a solution of 3-methoxycarbonylcyclobutanone (0.707 g, 5.52 mmol) and methyl isocyanoacetate (0.6 g, 6.07 mmol) in dry tetrahydrofuran (20 ml) over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours, cooled to 0° C. and 10% aqueous acetic acid (20 ml) added dropwise. The organic solvent was removed in vacuo and the resulting solution extracted with dichloromethane (3×20 ml). The combined extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated to give an oil. The crude product was purified by flash chromatography, eluting with ethyl acetate-hexane (1:1, 3:2), to give methyl N-formyl-α-(3-methoxycarbonylcyclobutylidene)glycinate as a colourless oil. was added dropwise cooled to 0° C. The organic solvent was removed in vacuo the resulting solution extracted with dichloromethane (3×20 ml) The combined extracts were washed with water dried over anhydrous magnesium sulphate evaporated to give an oil The crude product was purified by flash chromatography eluting with ethyl acetate-hexane (1:1, 3:2)

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

Procedure: A solution of methyl 3-oxocyclobutanecarboxylate (0.5 g, 3.90 mmol) in EtOAc (10 mL) was treated with dimethylamine (1M in THF, 11.71 mL, 11.71 mmol), stirred at RT for 1 h, treated portion-wise with sodium triacetoxyborohydride (1.158 g, 5.46 mmol) and stirred at RT overnight. The mixture was treated with 1N NaOH, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford methyl 3-(dimethylamino)cyclobutanecarboxylate (596 mg, 97%). 1H NMR (400 MHz, DMSO-d6): δ 3.57 (s, 3H), 3.33-3.26 (m, 1H), 2.75-2.74 (m, 1H), 2.19-2.18 (m, 2H), 1.97 (s, 6H), 1.88-1.85 (m, 2H). stirred at RT overnight extracted with EtOAc (3×) the combined organics were washed with brine dried over Na2SO4 concentrated to dryness

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

Procedure: Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tetrahydrofuran (12 L), 1,4-dibromobenzene (2020 g, 8.56 mol, 1.03 equiv), followed by the addition of n-BuLi (3566 mL, 1.03 equiv, 2.4 M) dropwise with stirring at −78° C. The mixture was stirred at −78° C. for 1 h. Into another 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 3-oxocyclobutane-1-carboxylate (1064 g, 8.30 mol, 1.00 equiv) in tetrahydrofuran (4 L). To this was added the resulting solution in the first flask dropwise with stirring at −78° C. The resulting solution was stirred overnight at 25° C. This reaction was repeated for 2 more times. The reaction was then quenched by the addition of 15 L of saturated aqueous NH4Cl, concentrated under vacuum, diluted with 15 L of H2O and extracted with 2×5 L of ethyl acetate. The organic layers were combined, washed with 1×8 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 6500 g (92%) of methyl 3-(4-bromophenyl)-3-hydroxycyclobutane-1-carboxylate as a dark red oil. Into a 20-L 4-necked round-bottom flask purged maintained with an inert atmosphere of nitrogen The mixture was stirred at −78° C. for 1 h Into another 20-L 4-necked round-bottom flask purged maintained with an inert atmosphere of nitrogen To this was added the resulting solution in the first flask dropwise with stirring at −78° C The resulting solution was stirred overnight at 25° C The reaction was then quenched by the addition of 15 L of saturated aqueous NH4Cl concentrated under vacuum diluted with 15 L of H2O extracted with 2×5 L of ethyl acetate washed with 1×8 L of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

Procedure: A solution of methyl 3-oxocyclobutanecarboxylate (4.60 g, 35.94 mmol), 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (11.0 g, 35.94 mmol) and Ti(iPrO)4 (4.0 g, 14.08 mmol) in MeOH (80 mL) was stirred at 45° C. for 2 h, then NaCNBH3 (4.5 g, 71.87 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with aq. sat. NaHCO3 (40 mL) and filtered, extracted with DCM (80 mL×3), dried over Na2SO4 and concentrated. The residue was purified by preparative-HPLC to obtain the title compound (6.2 g, Yield 41%). 1H NMR (500 MHz, CDCl3): δH 8.38-8.34 (m, 1H), 7.90 (s, 1H), 5.98 (d, J=3.0 Hz, 1H), 5.75 (br s, 2H), 5.48-5.46 (m, 1H), 5.03-5.01 (m, 1H), 4.35-4.33 (m, 1H), 3.69-3.66 (m, 3H), 3.50-3.17 (m, 1H), 3.05-2.73 (m, 3H), 2.48-2.44 (m, 2H), 1.95-1.91 (m, 2H), 1.62 (s, 3H), 1.39 (s, 3H) ppm; ESI-MS (m/z): 419.2[M+1]+. The reaction was quenched with aq. sat. NaHCO3 (40 mL) filtered extracted with DCM (80 mL×3) dried over Na2SO4 concentrated The residue was purified by preparative-HPLC

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

Procedure: A solution of methyl 3-oxocyclobutanecarboxylate (1.28 g crude), 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (2.0 g, 6.25 mmol) (Townsend et al Org Lett 2009, 11, 2976-2679) and Ti(iPrO)4 (1.78 g, 6.25 mmol) in MeOH (50 mL) was stirred at 45° C. for 2 h, then NaCNBH3 (0.79 g, 12.50 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with aq. sat. NaHCO3 (40 mL), filtered, extracted with DCM (40 mL×3), dried over Na2SO4 and concentrated. The residue was purified by SGC (DCM:MeOH=12:1) to obtain title compound (1.7 g, Yield 63%). 1H NMR (500 MHz, MeOD): δH 8.28-8.27 (m, 1H), 8.21 (s, 1H), 6.20-6.18 (m, 1H), 5.52 (dd, J=1.5, 6.0 Hz, 1H), 5.00 (dd, J=3.0, 6.0 Hz, 1H), 5.33 (brs, 1H), 3.65-3.63 (m, 3H), 2.77-2.55 (m, 4H), 2.19-2.11 (m, 5H), 2.00-1.82 (m, 2H), 1.59 (s, 3H), 1.38 (s, 3H) ppm; ESI-MS (m/z): 433.2[M+1]+. The reaction was quenched with aq. sat. NaHCO3 (40 mL) filtered extracted with DCM (40 mL×3) dried over Na2SO4 concentrated The residue was purified by SGC (DCM:MeOH=12:1)

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

Procedure: To a solution of DCC (5.96 g, 28.95 mmol) in DCM (20 ml) was added dropwise a mixture of 3-oxocyclobutanecarboxylic acid (3.0 g, 26.31 mmol), MeOH (1.68 g, 52.62 mmol) and DMAP (2.57 g, 21.05 mmol) in DCM (30 ml). The reaction mixture was stirred at RT overnight. The mixture was filtrated. The filtrate was washed with 0.5 M HCl solution (50 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by SGC (PE:EA=5:1) to obtain the title compound (4.0 g). 1H N.R (500 MHz, CDCl3): δ 3.77 (s, 3H), 3.42-3.26 (m, 5H) ppm. The mixture was filtrated The filtrate was washed with 0.5 M HCl solution (50 ml) The organic layer was dried over Na2SO4 concentrated The residue was purified by SGC (PE:EA=5:1)

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

Procedure: To a solution of DCC (5.96 g, 28.95 mmol) in DCM (20 ml) was added dropwise a mixture of 3-oxocyclobutanecarboxylic acid (3.0 g, 26.31 mmol), MeOH (1.68 g, 52.62 mmol) and DMAP (2.57 g, 21.05 mmol) in DCM (30 ml). The reaction mixture was stirred at RT overnight. The mixture was filtrated. The filtrate was washed with 0.5 M HCl solution (50 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by SGC (PE:EA=5:1) to obtain the title compound (4.0 g). 1H N.R (500 MHz, CDCl3): δ 3.77 (s, 3H), 3.42-3.26 (m, 5H) ppm. The mixture was filtrated The filtrate was washed with 0.5 M HCl solution (50 ml) The organic layer was dried over Na2SO4 concentrated The residue was purified by SGC (PE:EA=5:1)

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

Procedure: A solution of methyl 3-oxocyclobutanecarboxylate (4.60 g, 35.94 mmol), 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (11.0 g, 35.94 mmol) and Ti(iPrO)4 (4.0 g, 14.08 mmol) in MeOH (80 mL) was stirred at 45° C. for 2 h, then NaCNBH3 (4.5 g, 71.87 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with aq. sat. NaHCO3 (40 mL) and filtered, extracted with DCM (80 mL×3), dried over Na2SO4 and concentrated. The residue was purified by preparative-HPLC to obtain the title compound (6.2 g, Yield 41%). 1H NMR (500 MHz, CDCl3): δH 8.38-8.34 (m, 1H), 7.90 (s, 1H), 5.98 (d, J=3.0 Hz, 1H), 5.75 (br s, 2H), 5.48-5.46 (m, 1H), 5.03-5.01 (m, 1H), 4.35-4.33 (m, 1H), 3.69-3.66 (m, 3H), 3.50-3.17 (m, 1H), 3.05-2.73 (m, 3H), 2.48-2.44 (m, 2H), 1.95-1.91 (m, 2H), 1.62 (s, 3H), 1.39 (s, 3H) ppm; ESI-MS (m/z): 419.2 [M+1]+. The reaction was quenched with aq. sat. NaHCO3 (40 mL) filtered extracted with DCM (80 mL×3) dried over Na2SO4 concentrated The residue was purified by preparative-HPLC

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

Procedure: A solution of methyl 3-oxocyclobutanecarboxylate (1.28 g crude), 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (2.0 g, 6.25 mmol) (Townsend et al Org Lett 2009, 11, 2976-2679) and Ti(iPrO)4 (1.78 g, 6.25 mmol) in MeOH (50 mL) was stirred at 45° C. for 2 h, then NaCNBH3 (0.79 g, 12.50 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with aq. sat. NaHCO3 (40 mL), filtered, extracted with DCM (40 mL×3), dried over Na2SO4 and concentrated. The residue was purified by SGC (DCM:MeOH=12:1) to obtain title compound (1.7 g, Yield 63%). 1H NMR (500 MHz, MeOD): δH 8.28-8.27 (m, 1H), 8.21 (s, 1H), 6.20-6.18 (m, 1H), 5.52 (dd, J=1.5, 6.0 Hz, 1H), 5.00 (dd, J=3.0, 6.0 Hz, 1H), 5.33 (brs, 1H), 3.65-3.63 (m, 3H), 2.77-2.55 (m, 4H), 2.19-2.11 (m, 5H), 2.00-1.82 (m, 2H), 1.59 (s, 3H), 1.38 (s, 3H) ppm; ESI-MS (m/z): 433.2 [M+1]+. The reaction was quenched with aq. sat. NaHCO3 (40 mL) filtered extracted with DCM (40 mL×3) dried over Na2SO4 concentrated The residue was purified by SGC (DCM:MeOH=12:1)

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

Procedure: To a solution of DCC (5.96 g, 28.95 mmol) in DCM (20 ml) was added dropwise a mixture of 3-oxocyclobutanecarboxylic acid (3.0 g, 26.31 mmol), MeOH (1.68 g, 52.62 mmol) and DMAP (2.57 g, 21.05 mmol) in DCM (30 ml). The reaction mixture was stirred at RT overnight. The mixture was filtrated. The filtrate was washed with 0.5 M HCl solution (50 ml). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by SGC (PE: EA=5:1) to obtain the title compound (4.0 g). 1H N.R (500 MHz, CDCl3): δ 3.77 (s, 3H), 3.42-3.26 (m, 5H) ppm. The mixture was filtrated The filtrate was washed with 0.5 M HCl solution (50 ml) The organic layer was dried over Na2SO4 concentrated The residue was purified by SGC (PE: EA=5:1)