Chemical Synthesis of the Anti-COVID-19 Drug Remdesivir.

Remdesivir has become an important compound for the treatment of COVID-19. Here, we describe the catalytic asymmetric synthesis of this anti-COVID-19 drug. First, the P-racemic phosphoryl chloride is synthesized in a facile procedure. Then, it is possible to obtain the protected remdesivir via the organocatalytic asymmetric phosphorylation of protected nucleoside GS441524 with P-racemic phosphoryl chloride catalyzed by chiral bicyclic imidazole. Finally, remdesivir is easily prepared by deprotection.

INTRODUCTION

Recently, remdesivir, developed by Gilead Sciences using ProTide technology, has become one of the most effective anti‐COVID‐19 drugs. Thus far, two synthetic methods for remdesivir have been established (Siegel et al., 2017; Warren et al., 2016), but both of these methods require chiral resolution and additional synthetic steps, leading to resource waste and low synthetic efficiency. In 2012, our group developed the first catalytic asymmetric synthesis of P‐stereogenic phosphoric acid derivatives using chiral bicyclic imidazole organocatalysts (Liu et al., 2012). Inspired by this methodology for the construction of P‐stereocenters, we developed the first catalytic asymmetric synthesis of remdesivir via chiral bicyclic imidazole–catalyzed phosphorylation (Wang et al., 2020).

The core strategy in this protocol is to generate the S P‐isomer of protected remdesivir via catalytic asymmetric phosphorylation. Basic Protocol 1 describes the synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4. Basic Protocol 2 describes the synthesis of the chiral bicyclic imidazole Ad‐DPI. Basic Protocol 3 describes the synthesis of remdesivir.

Figures and some textual material are taken from our recently published work (Wang et al., 2020) and rewritten as step‐by‐step protocols to support reproduction of the original work.

This protocol describes the synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4 (Mackman, Parrish, Ray, & Theodore, 2012; Meppen et al., 2009), the phosphorylation reagent, which is derived from 2‐ethylbutan‐1‐ol (Fig. 1). The synthesis of rac‐4 involves two steps: (1) esterification of 2‐ethylbutan‐1‐ol 1 with l‐alanine to prepare 2‐ethylbutyl l‐alaninate hydrochloride salt 2 and (2) phosphorylation of 2‐ethylbutyl l‐alaninate hydrochloride salt 2 by phenyl dichlorophosphate 3 to obtain 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4.

Figure 1

Synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4.

NOTE: Anhydrous reaction conditions are required for the above two steps of this procedure. Glassware needs to be oven‐dried, and anhydrous solvents should be prepared or purchased in Sure/Seal bottles.

Materials

2‐Ethylbutan‐1‐ol (99.0%, Energy Chemical, A040495)

Thionyl chloride (SOCl2, 99.0%, Energy Chemical, W610261)

l‐alanine (99.0%, Energy Chemical, A070054)

Petroleum ether (AR, General‐Reagent, G84208C)

Anhydrous dichloromethane (CH2Cl2, >99.5%, General‐Reagent, G81014C)

Dry nitrogen

Phenyl dichlorophosphate (98%, Energy Chemical, A020205)

Triethylamine (Et3N, 99.5%, Energy Chemical, B010065)

Anhydrous ethyl ether (Et2O, >99.5%, Sinopharm Chemical Reagent, 10009318)

150‐, and 200‐ml two‐necked round‐bottomed flasks

Magnetic stirring bar

Magnetic stirrer

Magnetic stirrer with heating

150‐, and 200‐ml round‐bottomed flasks

Rotary vacuum evaporator

High‐vacuum oil pump

Syringe needle

Ice bath

Oil bath

Cryogenic cooling circulation pump

Vacuum filtration system

1H, 13C, and 31P NMR equipment or facilities

Add 75 ml (609.3 mmol) 2‐ethylbutan‐1‐ol 1 io a dry 200‐ml two‐necked round‐bottomed flask.

Add 10.9 ml (150.0 mmol) SOCl2 dropwise over 10 min to the flask containing 2‐ethylbutan‐1‐ol 1 at 0°C and stir the mixture for 1 hr at 0°C.

Weigh out 8.9 g (100.0 mmol) of l‐alanine into the flask containing the mixture at 0°C.

Raise the temperature of the reaction mixture to 90°C, stir the mixture for 16 hr at 90°C, and then allow it to cool to 25°C.

Transfer the reaction mixture into a dry 200‐ml round‐bottomed flask.

Evaporate the reaction mixture using a rotary evaporator.

Wash the reaction mixture with 20 ml petroleum ether twice.

Dry the resulting white solid for 1 hr in vacuo to obtain 2‐ethylbutyl l‐alaninate hydrochloride salt 2.

Weigh out 3.15 g (15.0 mmol) of 2 into a dry 150‐ml two‐necked round‐bottomed flask.

Add 50 ml anhydrous CH2Cl2 to the flask using a syringe needle.

Cool the temperature of reaction mixture to –80°C under dry nitrogen.

Add 2.24 ml (15.0 mmol) phenyl dichlorophosphate to the flask using a syringe needle.

Add 4.17 ml (30.0 mmol) Et3N to the flask using a syringe needle over 10 min, and stir the mixture for 30 min.

Raise temperature of reaction mixture to 25°C and stir it for 2 hr.

Transfer the reaction mixture into a dry 150‐ml round‐bottomed flask.

Evaporate the reaction mixture using a rotary evaporator to obtain a white solid.

Add 50 ml anhydrous Et2O to the flask and stir the mixture for 10 min.

Vacuum filter the mixture using a vacuum filtration system with the 150‐ml round‐bottomed flask to remove the solid.

Evaporate the filtrate using a rotary evaporator.

Dry the resulting colorless oil for 1 hr in vacuo to provide 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate rac‐4.

Characterize the product by 1H NMR, 13C NMR, and 31P NMR.

Product rac‐4 is a colorless oil (4.9 g, 94% yield). : δ 7.41‐7.34 (m, 2H), 7.29‐7.22 (m, 3H), 4.53‐4.33 (m, 1H), 4.26‐4.06 (m, 3H), 1.62‐1.48 (m, 4H), 1.40‐1.33 (m, 4H), and 0.95‐0.87 (m, 6H). : δ 173.0, 172.9, 172.8, 172.7, 149.9, 149.9, 149.9, 149.8, 149.8, 130.0, 129.9, 129.9, 129.9, 126.0, 126.0, 126.0, 120.6, 120.6, 68.0, 67.9, 50.9, 50.6, 50.6, 40.3, 23.3, 23.3, 23.3, 20.6, 20.6, 20.6, 20.6, 11.0, and 11.0. : δ 8.04 (s) and 7.69 (s).

This protocol describes the synthesis of chiral bicyclic imidazole Ad‐DPI (Wang et al., 2020; Wang, Zhang, Ling, Zhang, & Zhang, 2017; Zhang, Xie, Jia, & Zhang, 2010), the catalyst for asymmetric phosphorylation prepared from imidazole (Fig. 2). The synthesis involves three steps: (1) synthesis of (rac)‐HO‐DPI from acrolein and imidazole, (2) synthesis of (S)‐HO‐DPI via kinetic resolution catalyzed by Novozyme 435, and (3) synthesis of Ad‐DPI from (S)‐HO‐DPI.

Figure 2

Synthesis of chiral bicyclic imidazole Ad‐DPI.

Imidazole (99.0%, Energy Chemical, E020263)

1,4‐Dioxane (>99.5%, Sinopharm Chemical Reagent, 10008918)

Acetic acid (AcOH, >99.5%, Sinopharm Chemical Reagent, 10000218)

Acrolein (>98.0%, Senfeida, BXQ100500)

Silica gel (100‐200 Mesh)

Ethyl acetate (EtOAc, >99.5%, General‐Reagent, G23272D)

Methanol (MeOH, >99.5%, Sinopharm Chemical Reagent, 10014118)

Acetonitrile (MeCN, >99.0%, Sinopharm Chemical Reagent, 80000618)

Isopropenyl acetate (>98.0%, TCI, A0035)

Novozyme 435 (Shanghai Yuanye Bio‐Technology Co., Ltd, S27516‐10g)

Anhydrous tetrahydrofuran (THF, >99.0%, Sinopharm Chemical Reagent, 80124418)

Dry nitrogen

Sodium hydride (NaH, 60% dispersion in mineral oil, Energy Chemical, E060138)

1‐Isocyanatoadamantane (>98.0%, TCI, A1706)

Dichloromethane (CH2Cl2, >99.5%, General‐Reagent, G81014C)

Sodium sulfate (Na2SO4, >99.0%, General‐Reagent, G82667C)

Isopropanol (99.8%, Adamas‐Beta, 75885G)

Hexane (99.0%, Adamas‐Beta, 14153F)

100‐, and 250‐ml two‐necked round‐bottomed flasks

Reflux condensers

Magnetic stirring bar

Magnetic stirrer

Magnetic stirrer with heating

50‐, 100‐, and 250‐ml round‐bottomed flasks

Rotary vacuum evaporator

Flash chromatography columns

High‐vacuum oil pump

Vacuum filtration system

Ice bath

Oil bath

Syringe needle

1H and 13C NMR, HPLC, and high‐resolution mass spectrometry (HRMS) equipment or facilities

Additional reagents and equipment for silica gel flash chromatography (see Current Protocols article: Meyers, 2001)

Weigh out 1.6 g (23.9 mmol) imidazole into a 100‐ml two‐necked round‐bottomed flask.

Add 25 ml 1,4‐dioxane to this flask.

Add 0.1 ml (1.7 mmol) AcOH to the flask.

Add 2.5 ml (36.7 mmol) acrolein to the flask and stir the mixture.

Reflux the reaction mixture for 36 hr.

Transfer the reaction mixture into a 100‐ml round‐bottomed flask.

Evaporate the reaction mixture using a rotary evaporator.

Purify the crude product by silica gel chromatography (100‐200 Mesh; Meyers, 2001) using 3/1 (v/v) EtOAc/MeOH to obtain (rac)‐HO‐DPI.

Characterize the product by 1H NMR, 13C NMR, HRMS, and HPLC.

The product (rac)‐HO‐DPI is a white solid (2.4 g, 81% yield). : δ 7.07 (d, J = 1.2 Hz, 1 H), 6.85 (d, J = 1.2 Hz, 1 H), 5.23 (dd, J = 7.2 Hz, 3.2 Hz, 1 H), 4.24‐4.16 (m, 1 H), 3.98‐3.88 (m, 1 H), 3.00‐2.88 (m, 1 H), and 2.64‐2.54 (m, 1 H). : δ 156.5, 132.5, 114.3, 63.6, 43.2, and 36.3. HRMS (ESI): m/z calculated for C6H9N2O+ (M+H)+ 125.0709 was 125.0707. HPLC: Daicel CHIRALCEL OD‐H, 25 cm×4.6 μm; 0.5 ml/min isopropanol/hexane = 10/90, 210 nm; retention times: 19.1 min and 30.5 min.

Weigh out 5.0 g (40.0 mmol) (rac)‐HO‐DPI into a 250‐ml two‐necked round‐bottomed flask.

Add 150 ml of MeCN to the flask.

Add 21.8 ml (200.0 mmol) isopropenyl acetate to the flask.

Add 5.0 g Novozyme 435 to the flask.

Raise temperature of reaction mixture to 35°C and stir the mixture gently for 12 hr.

Vacuum filter the mixture using a vacuum filtration system with the 250‐ml round‐bottomed flask to remove the solid.

Evaporate the reaction mixture using a rotary evaporator to remove MeCN.

Purify the crude product by silica gel chromatography (100‐200 Mesh; Meyers, 2001) using 10:1 v/v EtOAc/MeOH to yield (S)‐HO‐DPI.

Characterize the product by 1H‐NMR, 13C‐NMR, and HPLC.

The product (S)‐HO‐DPI is a white solid (1.6 g, 32% yield). : δ 7.07 (d, J = 1.2 Hz, 1 H), 6.85 (d, J = 1.2 Hz, 1 H), 5.23 (dd, J = 7.2 Hz, 3.2 Hz, 1 H), 4.24‐4.16 (m, 1 H), 3.98‐3.88 (m, 1 H), 3.00‐2.88 (m, 1 H), and 2.64‐2.54 (m, 1 H). : δ 156.5, 132.5, 114.3, 63.6, 43.2, and 36.3. HPLC: 99.9% ee, Daicel CHIRALCEL OD‐H, 25 cm×4.6 μm; 0.5 ml/min, isopropanol/hexane = 10/90, 210 nm; retention times: 19.1 min (minor) and 30.5 min (major).

Weigh out 200 mg (1.6 mmol) (S)‐HO‐DPI into a dry 50‐ml two‐necked round‐bottomed flask.

Add 20 ml THF to the flask.

Cool the reaction mixture to 0°C under dry nitrogen.

Add 77 mg NaH (60% in mineral oil, 1.9 mmol) in portions over 30 min to the flask and stir the mixture for 1 hr.

Add 428 mg (2.4 mmol) 1‐isocyanatoadamantane to the flask.

Raise the temperature of the reaction mixture to 25°C and stir the mixture gently for 16 hr.

Add 30 ml water to the flask to quench the reaction.

Extract the mixture with 20 ml CH2Cl2 three times.

Dry the organic layer over Na2SO4 and remove the solid by filtration.

Evaporate the reaction mixture using a rotary evaporator to remove CH2Cl2.

Purify the crude product by silica gel chromatography (100‐200 Mesh; Meyers, 2001) using 10/1 v/v EtOAc/MeOH to obtain Ad‐DPI.

Characterize the product by 1H NMR, 13C NMR, and HRMS.

The product Ad‐DPI is a white solid (285 mg, 59% yield). : δ 7.18 (d, J = 1.3 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 5.86 (dd, J = 7.2, 2.7 Hz, 1H), 4.72 (s, 1H), 4.19‐4.06 (m, 1H), 4.03‐3.91 (m, 1H), 3.11‐2.98 (m, 1H), 2.66‐2.53 (m, 1H), 2.11‐2.05 (m, 3H), 1.95‐1.90 (m, 6H), 1.68‐1.64 (m, 6H). : δ 153.5, 151.7, 134.8, 115.5, 67.1, 51.0, 43.1, 42.6, 41.8, 36.6, 36.3, 35.4, 29.7, 29.5. HRMS (ESI): m/z calcd. for C17H24N3O2 + (M+H)+ 302.1863, found 302.1868.

This protocol describes the synthesis of remdesivir (Wang et al., 2020), the ProTide prodrug prepared from rac‐4 and nucleoside 5 (Fig. 3). The synthesis involves two steps: (1) catalytic asymmetric phosphorylation of nucleoside GS441524 5 with 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate (rac‐4) catalyzed by Ad‐DPI to prepare protected remdesivir S P‐6. (2) deprotection of S P‐6 with 37% HCl in THF to provide remdesivir (Warren et al., 2016).

Figure 3

Synthesis of remdesivir.

GS441524 (5, 98.0%, Aikonchem, AK01FWCB)

(S)‐6,7‐Dihydro‐5H‐pyrrolo[1,2‐a]imidazol‐7‐yl adamantan‐1‐ylcarbamate (Ad‐DPI, Basic Protocol 2)

4 Å molecular sieves

Dry nitrogen

Dichloromethane (CH2Cl2, >99.5%, General‐Reagent, G81014C)

2,6‐Lutidine (99.0%, Energy Chemical, W330004)

2‐Ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate (rac‐4; Basic Protocol 1)

Silica gel (100‐200 Mesh)

Petroleum ether (AR, General‐Reagent, G84208C)

Isopropyl ether (99.0%, Energy Chemical, W330208)

Ethyl acetate (EtOAc, >99.5%, General‐Reagent, G23272D)

Isopropanol

Hexane

Tetrahydrofuran (THF, >99.0%, Sinopharm Chemical Reagent, 80124418)

37% aqueous hydrochloric acid solution (Sinopharm Chemical Reagent, 10011061)

Saturated aqueous sodium bicarbonate solution (99.0%, Adamas‐Beta, 24073D)

Na2SO4 (>99.0%, General‐Reagent, G82667C)

100‐, and 1000‐ml two‐necked round‐bottomed flasks

Magnetic stirring bar

Magnetic stirrer

Magnetic stirrer with heating

500‐, and 1000‐ml round‐bottomed flasks

Rotary vacuum evaporator

High‐vacuum oil pump

Flash chromatography columns

Preparative HPLC column: Daicel CHIRALCEL IE, 1 cm × 25 cm

Separatory funnels

Ice bath

Oil bath

Syringe needle

Cryogenic cooling circulation pump

Vacuum filtration system

1H, 13C, and 31P NMR and HPLC and HRMS equipment or facilities

Additional reagents and equipment for silica gel flash chromatography (see Current Protocols article: Meyers, 2001)

Add 10.0 g (30.2 mmol) 5 to a dry 1000‐ml two‐necked round‐bottomed flask equipped with a magnetic stir bar.

Add 909.6 mg (3.0 mmol) Ad‐DPI to the flask.

Add 11.0 g 4 Å molecular sieve to the flask.

Evacuate and backfill the flask with dry nitrogen three times.

Add 300 ml CH2Cl2 to the flask with the aid of a syringe needle.

Add 7.0 ml (60.4 mmol) 2,6‐lutidine to the flask with the aid of a syringe needle.

Cool the temperature of reaction mixture to –40°C under dry nitrogen and stir the mixture for 10 min.

Add 15.7 g (45.3 mmol) rac‐4 to the flask with the aid of a syringe needle and stir the reaction mixture for 48 hr.

Add 30 ml water to the flask to quench the reaction.

Transfer the reaction mixture into a 1000‐ml round‐bottomed flask.

Evaporate the reaction mixture using a rotary evaporator and concentrate the residue in vacuo using a high‐vacuum oil pump.

Analyze the crude product by 31P NMR showing a d.r. of 21.2:1.

Purify the crude product by silica gel chromatography (100‐200 Mesh) using 1/5 v/v petroleum ether/ethyl acetate and then recrystallize the product from dichloromethane/isopropyl ether at –30°C to provide protected remdesivir S P‐6 as a white solid (16.5 g, 85% yield, >99:1 d.r.).

Purify the residue from mother liquor by preparative HPLC (Daicel CHIRALCEL IE, 1 cm × 25 cm, 10 ml/min, isopropanol/hexane = 30/70, 220 nm, collected from 49.2 to 63.9 min) to yield S p‐6 as a white solid (0.8 g, 4% yield, >99:1 d.r.).

Combine two parts of product providing 17.3 g S p‐6 (89% yield, >99:1 d.r.).

Characterize the product by 1H NMR, 13C NMR, 31P NMR, HPLC, and HRMS.

The product Sp‐6 is a white solid (17.3 g, 89% yield, >99:1 d.r.). : δ 7.88 (s, 1H), 7.29‐7.23 (m, 2H), 7.17‐7.10 (m, 3H), 6.93‐6.90 (m, 2H), 5.33 (d, J = 6.7 Hz, 1H), 4.98 (dd, J = 6.6, 3.4 Hz, 1H), 4.60‐4.55 (m, 1H), 4.36‐4.25 (m, 2H), 4.02 (dd, J = 10.9, 5.8 Hz, 1H), 3.91 (dd, J = 10.9, 5.7 Hz, 1H), 3.88‐3.79 (m, 1H), 1.70 (s, 3H), 1.49‐1.41 (m, 1H), 1.39 (s, 3H), 1.35‐1.24 (m, 8H), and 0.85 (t, J = 7.5 Hz, 6H). : δ 174.9, 174.8, 156.6, 152.0, 151.9, 147.6, 130.6, 126.0, 124.9, 121.3, 121.2, 118.0, 117.7, 116.9, 112.5, 103.0, 85.7, 84.8, 84.8, 83.0, 82.5, 68.1, 67.0, 66.9, 51.4, 41.6, 26.5, 25.6, 24.2, 24.1, 20.5, 20.4, 11.3, and 11.3. : δ 3.23 (s). HPLC analysis: >99:1 d.r. [Daicel CHIRALPAK IE column; 4.6 μm×25 cm; solvent system: isopropanol/hexane = 30/70; 1.0 ml/min; retention times: 21.2 min (minor) and 26.5 min (major)]. HRMS (ESI): m/z calculated for C30H40N6O8P+ (M+H)+ 643.2640 was 643.2609.

Weigh out 1.2 g (1.8 mmol) S p‐6 into a 100‐ml two‐necked round‐bottomed flask.

Add 24 ml THF to the flask.

Cool the reaction mixture to 0°C and stir the mixture.

Add 2.1 ml 37% aqueous hydrochloric acid solution slowly to the flask.

Raise temperature of reaction mixture to 25°C and stir the mixture for 8 hr.

Transfer the reaction mixture into a 500‐ml round‐bottomed flask and dilute the reaction mixture with 60 ml water.

Add saturated aqueous sodium bicarbonate solution to adjust the pH of reaction mixture to 8.

Extract the resulting mixture with 60 ml ethyl acetate three times.

Dry the combined organic phase over Na2SO4 and remove the solid by filtration.

Evaporate the reaction mixture using a rotary evaporator.

Purify the crude product by silica gel chromatography (100‐200 Mesh) using 1/3 v/v) petroleum ether/ethyl acetate to provide remdesivir.

Characterize the product by 1H NMR, 13C NMR, 31P NMR, and high‐resolution mass spectrometry (HRMS).

The product remdesivir is a white solid (0.82 g, 73% yield). : δ 7.87 (s, 1H), 7.33‐7.27 (m, 2H), 7.21‐7.12 (m, 3H), 6.91 (d, J = 4.6 Hz, 1H), 6.88 (d, J = 4.6 Hz, 1H), 4.79 (d, J = 5.4 Hz, 1H), 4.44‐4.35 (m, 2H), 4.33‐4.25 (m, 1H), 4.20‐4.15 (m, 1H), 4.02 (dd, J = 10.9, 5.8 Hz, 1H), 3.95‐3.85 (m, 2H), 1.49‐1.40 (m, 1H), 1.34‐1.27 (m, 8H), 0.85 (t, J = 7.5 Hz, 6H). : δ 175.0, 174.9, 157.1, 152.1, 152.1, 148.2, 130.7, 126.0, 125.5, 121.3, 121.3, 117.9, 117.6, 112.3, 102.7, 84.3, 84.2, 81.2, 75.6, 71.6, 68.1, 67.2, 67.1, 51.5, 41.6, 24.2, 24.2, 20.6, 20.5, 11.3, 11.3. : δ 3.52 (s). HRMS (ESI): m/z calcd. for C27H36N6O8P+ (M+H)+ 603.2327, found 603.2300.

COMMENTARY

Background Information

Remdesivir is one of the most effective treatments for COVID‐19 (Holshue et al., 2020), which attracts researchers to develop an effective synthetic approach for this compound. Until now, two synthetic methods for remdesivir have been established (Siegel et al., 2017; Warren et al., 2016). Both of these methods require not only chiral resolution but also additional synthetic steps, which lead to the waste of resources and low synthetic efficiency. In 2010, a novel chiral bicyclic imidazole organocatalyst was developed by our group (Zhang et al., 2010). Over the past decade, this kind of organocatalyst was successfully applied in a number of asymmetric reactions (Liu et al., 2012; Wang et al., 2017; Wang et al., 2020; Wang, Zhang, Liu, Xie, & Zhang, 2014; Wang, Zhang, Xie, & Zhang, 2014; Wang, Zhou, Zhang, Zhang, & Zhang, 2020; Zhang et al., 2019; Zhang, Wang, Xie, Sun, & Zhang, 2014; Zhou et al., 2019; Zhou et al., 2021). In 2012, the first catalytic asymmetric synthesis of P‐stereogenic phosphoric acid derivatives was developed by our group using the chiral bicyclic imidazole catalyst (Liu et al., 2012). Later, scientists at Merck & Co. utilized bicyclic imidazole catalyst in the asymmetric synthesis of nucleoside‐based phosphoramidate prodrugs (DiRocco et al., 2017). Inspired by our previous work, we successfully developed the first catalytic asymmetric synthesis of remdesivir using the chiral bicyclic imidazole Ad‐DPI (Wang et al., 2020).

Critical Parameters and Troubleshooting

In Basic Protocol 1, both steps are sensitive to water. In Basic Protocol 2, the step for synthesis of Ad‐DPI is sensitive to water. In Basic Protocol 3, the catalytic asymmetric synthesis of S P‐6 step is sensitive to water. Anhydrous reaction conditions are required for the aforementioned steps. Glassware needs to be oven‐dried, and anhydrous solvents should be prepared or purchased in Sure/Seal bottles. In the step for synthesis of S P‐6 in Basic Protocol 3, 4 Å molecular sieves are necessary for the reaction.

Understanding Results

After the synthesis, the purified compounds are identified by 1H‐NMR, 13C‐NMR, and HRMS as shown in each synthesis. The d.r. value of crude S p‐6 is analyzed by 31P‐NMR. The optically pure S p‐6 is verified by 31P‐NMR and HPLC.

Time Considerations

Synthesis of 2‐ethylbutyl (chloro(phenoxy)phosphoryl)‐l‐alaninate (rac‐4) (Basic Protocol 1) can be completed within 28 hr. Synthesis of chiral bicyclic imidazole Ad‐DPI (Basic Protocol 2) can be completed within 4 days. Synthesis of remdesivir (Basic Protocol 3) can be completed within 3 days.

Author Contributions

Mo Wang: investigation, writing original draft; Lu Zhang: investigation; Xiaohong Huo: writing review and editing; Zhenfeng Zhang: writing review and editing; Wanbin Zhang: project administration, writing review and editing.

Conflict of Interest

The authors declare no conflict of interest.