Correction to “Stereoselective Synthesis of Nucleotide Analog Prodrugs (ProTides) via an Oxazaphospholidine Method”
Monta Nakamura, Kiyoshi Kakuta, Kazuki Sato, Takeshi Wada
Abstract
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Figure 7- —Japan Agency for Medical Research and Development10.13039/100009619
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TopicsOrganophosphorus compounds synthesis · DNA and Nucleic Acid Chemistry · Chemical Synthesis and Analysis
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 ^1^H, ^13^C, and ^31^P NMR spectra and experimental details for the 5′-oxazaphospholidine derivatives.
We express sincere regret for these errors in the published article.
Corrected Table of Contents graphic/graphical Abstract:
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 CH_3_CN (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 CH_3_CN (0.6 mL) was added to the reaction mixture at −40 °C and stirred for 5 min, then 1.0 M CH_3_CN 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 CH_2_Cl_2_ (30 mL) and washed with 0.2 M citric acid aqueous solution (30 mL) and saturated NaHCO_3_ aqueous solution (30 mL). The organic layer was dried over Na_2_SO_4_, 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 CD_3_CN (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 CD_3_CN (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 CD_3_CN (0.1 mL) was added to the reaction mixture at −40 °C and stirred for 5 min, then 3.3 M CD_3_CN 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 NaHCO_3_ aqueous solution (3 × 10 mL). The organic layer was dried over Na_2_SO_4_, 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 CH_3_CN (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 CH_3_CN (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 CH_3_CN 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