(1R,2R)-2-phenylmethoxycyclopentan-1-amine

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

Procedure: To a solution of (1R,2R)-2-benzyloxycyclopentylamine (1.0 g, 5.2 mmol) in tetrahydrofuran (12 mL) was slowly added 1,3-propanesultone (601 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×15 mL). The product was suspended in EtOH and the solvent was evaporated (to remove THF residue). The solid was dried in vacuo, affording the title compound (717 mg, 46%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.53 (d, 1H, J=11.2 Hz), 4.42 (d, 1H, J=11.2 Hz), 4.02 (m, 1H), 3.36 (m, 1H), 3.01 (t, 2H, J=7.8 Hz), 2.81 (t, 2H, J=7.8 Hz), 2.01 (m, 4H), 1.65 (m, 3H), 1.49 (m, 1H). 13C NMR (D2O, 125 MHz) δ ppm 137.00, 129.07, 129.01, 128.77, 81.78, 71.81, 63.89, 48.02, 45.34, 29.93, 27.43, 21.61, 20.94. [α]D=−38.8° (c=0.00122 in water). ES-MS 314 (M+1). at reflux for 2 hours The solid was collected by filtration washed with acetone (2×15 mL) the solvent was evaporated (to remove THF residue) The solid was dried in vacuo

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

Procedure: To a solution of (1R,2R)-2-(benzyloxy)cyclopentanamine (3.5 g, 18.3 mmol) in EtOH (20 mL) was added TFA (1.6 mL, 21.5 mmol), followed by Pd(OH)2/C (20% wt, 627 mg). The reaction mixture was degassed with Ar and stirred at rt under H2 atmosphere for 3 days. The resulting solid was filtered and rinsed with EtOH. The filtrate was concentrated to yield (1R,2R)-2-aminocyclopentanol TFA salt (4.3 g, 100% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-D6) ppm 1.00-1.13 (m, 1H), 1.39-1.57 (m, 2H), 1.56-1.76 (m, 2H), 1.79-1.94 (m, 1H), 1.94-2.10 (m, 1H), 3.06-3.23 (m, 1H), 3.88-4.02 (m, 1H), 7.84-8.07 (m, 2H). The reaction mixture was degassed with Ar The resulting solid was filtered rinsed with EtOH The filtrate was concentrated

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

Procedure: To a solution of 6-chloropurine riboside (10.0 g, 35 mmol) in ethanol (350 mL) was added triethylamine (10.0 mL, 100 mmol) and (1R,2R)-2-(benzyloxy)-cyclopentylamine (5.2 g, 52 mmol). The mixture was refluxed for 24 hours, during which the reaction went from a suspension to a clear solution. The ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water (100 mL:200 mL). The organic layer was separated and the aqueous layer washed with ethyl acetate (2×75 mL). The combined organic layers were dried (sodium sulfate), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and product precipitated by addition of hexane, to afford 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol as a white solid, (12.0 grams, 77%). The mixture was refluxed for 24 hours, during which the reaction The ethanol was removed under reduced pressure the residue was partitioned between ethyl acetate and water (100 mL:200 mL) The organic layer was separated the aqueous layer washed with ethyl acetate (2×75 mL) The combined organic layers were dried (sodium sulfate) the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (150 mL) product precipitated by addition of hexane

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

Procedure: To a solution of 6-chloropurine riboside (10.0 g, 35 mmol) in ethanol (350 mL) was added triethylamine (10.0 mL, 100 mmol) and (1R,2R)-2-(benzyloxy)-cyclopentylamine (5.2 g, 52 mmol). The mixture was refluxed for 24 hours, during which the reaction went from a suspension to a clear solution. The ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water (100 mL:200 mL). The organic layer was separated and the aqueous layer washed with ethyl acetate (2×75 mL). The combined organic layers were dried (sodium sulfate), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and product precipitated by addition of hexane, to afford 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol as a white solid, (12.0 grams, 77%). The mixture was refluxed for 24 hours, during which the reaction The ethanol was removed under reduced pressure the residue was partitioned between ethyl acetate and water (100 mL:200 mL) The organic layer was separated the aqueous layer washed with ethyl acetate (2×75 mL) The combined organic layers were dried (sodium sulfate) the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (150 mL) product precipitated by addition of hexane

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

Procedure: To a solution of 6-chloropurine riboside (10.0 g, 35 mmol) in ethanol (350 mL) was added triethylamine (10.0 mL, 100 mmol) and (1R,2R)-2-(benzyloxy)-cyclopentylamine (5.2 g, 52 mmol). The mixture was refluxed for 24 hours, during which the reaction went from a suspension to a clear solution. The ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water (100 mL:200 mL). The organic layer was separated and the aqueous layer washed with ethyl acetate (2×75 mL). The combined organic layers were dried (sodium sulfate), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and product precipitated by addition of hexane, to afford 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol as a white solid. The mixture was refluxed for 24 hours, during which the reaction The ethanol was removed under reduced pressure the residue was partitioned between ethyl acetate and water (100 mL:200 mL) The organic layer was separated the aqueous layer washed with ethyl acetate (2×75 mL) The combined organic layers were dried (sodium sulfate) the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (150 mL) product precipitated by addition of hexane

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

Procedure: To a solution of 6-chloropurine riboside (10.0 g, 35 mmol) in ethanol (350 mL) was added triethylamine (10.0 mL, 100 mmol) and (1R,2R)-2-(benzyloxy)-cyclopentylamine (5.2 g, 52 mmol). The mixture was refluxed for 24 hours, during which the reaction went from a suspension to a clear solution. The ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water (100 mL:200 mL). The organic layer was separated and the aqueous layer washed with ethyl acetate (2×75 mL). The combined organic layers were dried (sodium sulfate), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and product precipitated by addition of hexane, to afford 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol as a white solid. The mixture was refluxed for 24 hours, during which the reaction The ethanol was removed under reduced pressure the residue was partitioned between ethyl acetate and water (100 mL:200 mL) The organic layer was separated the aqueous layer washed with ethyl acetate (2×75 mL) The combined organic layers were dried (sodium sulfate) the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (150 mL) product precipitated by addition of hexane

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

Procedure: To a solution of (1R,2R)-2-benzyloxycyclopentylamine (1.0 g, 5.2 mmol) in tetrahydrofuran (12 mL) was slowly added 1,3-propanesultone (601 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×15 mL). The product was suspended in EtOH and the solvent was evaporated (to remove THF residue). The solid was dried in vacuo, affording the title compound (717 mg, 46%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.53 (d, 1H, J=11.2 Hz), 4.42 (d, 1H, J=11.2 Hz), 4.02 (m, 1H), 3.36 (m, 1H), 3.01 (t, 2H, J=7.8 Hz), 2.81 (t, 2H, J=7.8 Hz), 2.01 (m, 4H), 1.65 (m, 3H), 1.49 (m, 1H). 13C NMR (D2O, 125 MHz) δ ppm 137.00, 129.07, 129.01, 128.77, 81.78, 71.81, 63.89, 48.02, 45.34, 29.93, 27.43, 21.61, 20.94. [α]D=−38.8° (c=0.00122 in water). ES-MS 314 (M+1). at reflux for 2 hours The solid was collected by filtration washed with acetone (2×15 mL) the solvent was evaporated (to remove THF residue) The solid was dried in vacuo

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

Procedure: To a solution of (1R,2R)-2-(benzyloxy)cyclopentanamine (3.5 g, 18.3 mmol) in EtOH (20 mL) was added TFA (1.6 mL, 21.5 mmol), followed by Pd(OH)2/C (20% wt, 627 mg). The reaction mixture was degassed with Ar and stirred at rt under H2 atmosphere for 3 days. The resulting solid was filtered and rinsed with EtOH. The filtrate was concentrated to yield (1R,2R)-2-aminocyclopentanol TFA salt (4.3 g, 100% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-D6) ppm 1.00-1.13 (m, 1H), 1.39-1.57 (m, 2H), 1.56-1.76 (m, 2H), 1.79-1.94 (m, 1H), 1.94-2.10 (m, 1H), 3.06-3.23 (m, 1H), 3.88-4.02 (m, 1H), 7.84-8.07 (m, 2H). The reaction mixture was degassed with Ar The resulting solid was filtered rinsed with EtOH The filtrate was concentrated

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

Procedure: To a solution of 6-chloropurine riboside (10.0 g, 35 mmol) in ethanol (350 mL) was added triethylamine (10.0 mL, 100 mmol) and (1R,2R)-2-(benzyloxy)-cyclopentylamine (5.2 g, 52 mmol). The mixture was refluxed for 24 hours, during which the reaction went from a suspension to a clear solution. The ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water (100 mL:200 mL). The organic layer was separated and the aqueous layer washed with ethyl acetate (2×75 mL). The combined organic layers were dried (sodium sulfate), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and product precipitated by addition of hexane, to afford 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol as a white solid. The mixture was refluxed for 24 hours, during which the reaction The ethanol was removed under reduced pressure the residue was partitioned between ethyl acetate and water (100 mL:200 mL) The organic layer was separated the aqueous layer washed with ethyl acetate (2×75 mL) The combined organic layers were dried (sodium sulfate) the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (150 mL) product precipitated by addition of hexane

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

Procedure: To a solution of 6-chloropurine riboside (10.0 g, 35 mmol) in ethanol (350 mL) was added triethylamine (10.0 mL, 100 mmol) and (1R,2R)-2-(benzyloxy)-cyclopentylamine (5.2 g, 52 mmol). The mixture was refluxed for 24 hours, during which the reaction went from a suspension to a clear solution. The ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water (100 mL:200 mL). The organic layer was separated and the aqueous layer washed with ethyl acetate (2×75 mL). The combined organic layers were dried (sodium sulfate), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and product precipitated by addition of hexane, to afford 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol as a white solid. The mixture was refluxed for 24 hours, during which the reaction The ethanol was removed under reduced pressure the residue was partitioned between ethyl acetate and water (100 mL:200 mL) The organic layer was separated the aqueous layer washed with ethyl acetate (2×75 mL) The combined organic layers were dried (sodium sulfate) the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (150 mL) product precipitated by addition of hexane

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

Procedure: To a solution of 6-chloropurine riboside (10.0 g, 35 mmol) in ethanol (350 mL) was added triethylamine (10.0 mL, 100 mmol) and (1R,2R)-2-(benzyloxy)-cyclopentylamine (5.2 g, 52 mmol). The mixture was refluxed for 24 hours, during which the reaction went from a suspension to a clear solution. The ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water (100 mL:200 mL). The organic layer was separated and the aqueous layer washed with ethyl acetate (2×75 mL). The combined organic layers were dried (sodium sulfate), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and product precipitated by addition of hexane, to afford 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol as a white solid. The mixture was refluxed for 24 hours, during which the reaction The ethanol was removed under reduced pressure the residue was partitioned between ethyl acetate and water (100 mL:200 mL) The organic layer was separated the aqueous layer washed with ethyl acetate (2×75 mL) The combined organic layers were dried (sodium sulfate) the solvent was removed under reduced pressure The residue was dissolved in ethyl acetate (150 mL) product precipitated by addition of hexane

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

Procedure: To a solution of (1R,2R)-2-(benzyloxy)cyclopentanamine (3.5 g, 18.3 mmol) in EtOH (20 mL) was added TFA (1.6 ml, 21.5 mmol), followed by addition of Pd(OH)2/C (20% wt, 627 mg). The reaction mixture was degassed and stirred at ambient temperature under H2 for 3 days, then the solid was removed by filtration and the residue was rinsed with EtOH. The filtrate was concentrated to yield (1R,2R)-2-aminocyclopentanol TFA salt as a yellow oil. (4.3 g, 100%). NMR: 400 MHz 1H (DMSO-D6) 7.96 ppm, 2H, m; 3.95 ppm, 1H, m; 3.17 ppm, 1H, m; 2.02 ppm, 1H, m; 1.87 ppm, 1H, m; 1.66 ppm, 2H, m; 1.48 ppm, 2H, m; 1.07 ppm, 1H, m. The reaction mixture was degassed the solid was removed by filtration the residue was rinsed with EtOH The filtrate was concentrated