In the original publication, the stereochemistries of the 5′-oxazaphospholidine derivatives 4b–4d were incorrect. Our re-evaluation of the stereochemical pathway of phosphoramidates from 5′-oxazaphospholidine derivatives revealed an inconsistency in the original manuscript. To address this, we conducted a detailed review of the compounds used in this study.
Then, we became aware that we utilized (Rp)-5′-oxazaphospholidine derivatives as (Sp)-counterparts, and vice versa. Thus, (Sp)-ProTides were not synthesized from “(Sp)-5′-oxazaphospholidine derivatives” but from “(Rp)-5′-oxazaphospholidine derivatives”, and the original assignments of 5′-oxazaphospholidine derivatives ( R p)-4b, ( R p)-4c, ( S p)-4b, ( S p)-4c, and ( S p)-4d in Tables 2 and 3 should be replaced as ( S p)-4b, ( S p)-4c, ( R p)-4b, ( R p)-4c, and ( R p)-4d.
On the other hand, the stereochemical assignment of the 5′-oxazaphospholidine derivative ( R p)-4a in the original Schemes 2 and 3 and Table 1 was correct; however, the stereochemical assignments of the intermediates were incorrect. Based on the stereochemical pathway from 5′-oxazaphospholidine derivatives to ProTides, the (Sp)-model compound 13a and the (Rp)-model compound 13b were synthesized from the (Rp)-5′-oxazaphospholidine derivative ( R p)-4a and the (Sp)-5′-oxazaphospholidine derivative ( S p)-4a, respectively.
These errors also affect the graphical abstract, Experimental Section, and Supporting Information. We present herein the corrected stereochemistries of these compounds (Schemes – and Tables –); the corrected experimental details for 13a, 13b, and the general procedure for the synthesis of ProTides; and revised Supporting Information with the corrected 1H, 13C, and 31P NMR spectra and experimental details for the 5′-oxazaphospholidine derivatives.
1. Stereoselective Synthesis of Remdesivir (Part C, Corrected).
3. Synthesis of the Model Compound via Acylation of a Phosphite Triester (Corrected).
1. Investigation of Halogenation Reaction Conditions (Corrected).
| Entry | Solvent | Temp (°C) | 31P NMR yield of 13 (%) | Isolated yield of 13 (%) | dr |
|---|---|---|---|---|---|
| 1 | CD3CN | 0 | 28 | – | 70:30 |
| 2 | CD3CN | –20 | 36 | 16 | 88:12 |
| 3 | CD3CN | –40 | 53 | 25 | >99:1 |
| 4 | CH3CN-toluene | –40 | 78 | 39 | >99:1 |
Entries 1–3 and Entry 4 were conducted on 0.03 and 0.18 mmol scales, respectively.
Entry 1: Determined from the 31P NMR spectrum of crude mixture. Entries 2 and 3: Determined from the 31P NMR spectra after purification. Entry 4 was determined from RP-HPLC after deprotection of the DMTr group of the model compound.
All reagents were added as CH3CN solution.
3. Synthesis Results of Sofosbuvir, PSI-7976, and NUC-1031 (Corrected).
| Product | Scale (mmol) | 31P NMR yield of 16 (%) | Isolated yield of product (%) | dr |
|---|---|---|---|---|
| (Sp)-2 | 0.16 | 86 | 35 | >99:1 |
| (Rp)-2 | 1.0 | 88 | 46 | >99:1 |
| (Sp)-3 | 0.10 | 85 | 63 | >99:1 |
Determined from the 31P NMR spectra of crude mixtures.
Determined from the 31P NMR spectra after purification.
We express sincere regret for these errors in the published article.
Corrected Table of Contents graphic/graphical Abstract:
2. Synthesis of the Model Compound via an H-Phosphonate (Corrected).
2. Investigation of the Condensation Conditions of Compound 4b (Corrected).
| Entry | Scale (mmol) | Solvent | Time (min) | 31P NMR yield of 16b (%) | Isolated yield of 1 (%) | dr |
|---|---|---|---|---|---|---|
| 1 | 0.10 | CH3CN | 10 | 34 | – | >99:1 |
| 2 | 0.10 | CH3CN-toluene | 30 | 51 | – | >99:1 |
| 3 | 0.10 | CH3CN-toluene | 60 | 87 | 26 | >99:1 |
| 4 | 1.1 | CH3CN-toluene | 60 | 87 | 42 | >99:1 |
( S p)-4b and ( R p)-4b were used in Entries 1–3 and Entry 4, respectively.
Determined from the 31P NMR spectra of crude mixtures.
Determined from the 31P NMR spectra of crude mixtures.
Extraction in 0.2 M citric acid aqueous solution.
Determined from the 31P NMR spectra after purification.
Experimental Section
General Information
Corrected for 13a and 13b:
2-Ethylbutyl (S)-(((3aR,4R,6R,6aR)-6-(6-((bis(4-methoxyphenyl)(phenyl)methyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-l-alaninate (13a)
Compound ( R p)-4a (168.8 mg, 0.20 mmol) was dissolved in toluene (1.4 mL), dried over MS 4A for 24 h, and cooled to −40 °C. A mixture of CMPT (102.5 mg, 0.39 mmol) and PhOH (19.0 mg, 0.20 mmol) in CH3CN (0.7 mL), which was dried over MS 3A for 24 h, was added over 1 min to the solution. After stirred for 10 min at −40 °C, NBS (39.5 mg, 0.22 mmol) in CH3CN (0.6 mL) was added to the reaction mixture at −40 °C and stirred for 5 min, then 1.0 M CH3CN solution of l-alanine ester 8b (1.0 mL, 1.0 mmol) was added to the reaction mixture and stirred at room temperature for 6 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with 0.2 M citric acid aqueous solution (30 mL) and saturated NaHCO3 aqueous solution (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude 13a (223.7 mg). The residue (168.6 mg) was purified by silica gel column chromatography (neutral silica gel 40–50 μm, 10 g) using toluene–EtOAc (7:3, v/v containing 1% triethylamine) as an eluent to give 13a as a colorless foam (53.5 mg, 37%) (dr >99:1). Please refer to the revised Supporting Information for the spectral data.
2-Ethylbutyl((R)-(((3aR,4R,6R,6aR)-6-(6-((bis(4-methoxyphenyl)(phenyl)methyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-l-alaninate (13b)
Compound ( S p)-4a (84.4 mg, 0.10 mmol) was dissolved in CD3CN (0.3 mL), dried over MS 3A for 24 h, and cooled to −40 °C. A mixture of CMPT (52.3 mg, 0.20 mmol) and PhOH (9.3 mg, 0.10 mmol) in CD3CN (0.3 mL), which was dried over MS 3A for 24 h, was added to the solution. After stirred for 10 min at −40 °C, NBS (19.6 mg, 0.11 mmol) in CD3CN (0.1 mL) was added to the reaction mixture at −40 °C and stirred for 5 min, then 3.3 M CD3CN solution of l-alanine ester 8b (0.15 mL, 5.0 mmol) was added to the reaction mixture and stirred at room temperature for 3 h. The mixture was diluted with EtOAc (10 mL) and washed with saturated NaHCO3 aqueous solution (3 × 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (neutral silica gel, 40 g) using toluene–EtOAc (8:2–7:3, v/v) as an eluent and preparative TLC (hexane–EtOAc 7:3, v/v) to give 13b as a colorless foam (23.0 mg, 25%) (dr = 99:1). Please refer to the revised Supporting Information for the spectral data.
General Procedure of the Synthesis of ProTides
Compound ( R p)-4b (0.95 g, 1.1 mmol), ( S p)-4b (88.4 mg, 0.10 mmol), ( R p)-4c (98.5 mg, 0.16 mmol), ( S p)-4c (0.61 g, 1.0 mmol), or ( R p)-4d (90.3 mg, 0.10 mmol) was dissolved in toluene (0.7 mL for the synthesis of ( R p)-1 and 3; 7.0 mL for the synthesis of ( S p)-1 and ( R p)-2; and 1.4 mL for the ( S p)-2), dried over MS 4A for 2 h, and cooled to −40 °C. A mixture of CMPT (0.56 g, 2.2 mmol for ( S p)-1; 51.1 mg, 0.20 mmol for ( R p)-1; 86.2 mg, 0.33 mmol for ( S p)-2; 0.52 g, 2.0 mmol for ( R p)-2; and 53.5 mg, 0.21 mmol for 3) and PhOH (0.11 g, 1.2 mmol for ( S p)-1; 11.2 mg, 0.12 mmol for ( R p)-1; 16.8 mg, 0.18 mmol for ( S p)-2; 0.10 g, 1.1 mmol for ( R p)-2; and 11.3 mg, 0.12 mmol for 3) in CH3CN (3,0 mL for ( S p)-1 and ( R p)-2; 0.3 mL for ( R p)-1 and 3; and 0.6 mL for ( S p)-2), which was dried over MS 3A for 24 h, was added to the solution. After stirred for designated time (1 h for ( S p)-1 and ( R p)-1; 2 h for ( S p)-2 and ( R p)-2; and 3 h for 3) at −40 °C, NBS (194.9 mg, 1.1 mmol for ( S p)-1; 19.7 mg, 0.11 mmol for ( R p)-1; 0.45 mg, 0.16 mmol for ( S p)-2; 0.20 g, 1.1 mmol for ( R p)-2; and 19.8 mg, 0.11 mmol for 3) in CH3CN (3.0 mL for ( S p)-1 and ( R p)-2; 0.3 mL for ( R p)-1 and 3; and 0.6 mL for ( S p)-2) was added to the reaction mixture at −40 °C and stirred for 5 min, then CH3CN solution of l-alanine ester (8b (5.0 mL, 5.0 mmol) for ( S p)-1; 8b (1.0 mL, 0.05 mmol) for ( R p)-1; 8c (1.0 mL, 1.0 mmol) for ( S p)-2; 8c (5.0 mL, 5.0 mmol) for ( R p)-2; and 8d (0.5 mL, 0.5 mmol) for 3) was added to the reaction mixture and stirred at room temperature for 5 min.
Supplementary Material
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c02213.
Experimental details, HPLC profiles, copies of 1H, 13C, and 31P NMR spectra of new compounds and final products (corrected) (PDF)
Associated Data
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