Diethyl (2S,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate (CAS NO.: 174682-54-3) could be produced through the following synthetic routes.

A. Diethyl (2S,3S)-2-bromo-3-hydroxysuccinate (CAS NO.: 80640-14-8)(2). In an oven-dried, 300-mL, round-bottomed flask containing a -coated stirring bar is placed 26.0 g (0.126 mol) of diethyl L-tartrate. A pressure-equalizing dropping funnel containing 100 mL (0.504 mol) of 30% hydrobromic acid (HBr) in acetic acid is mounted on the flask and the top of the funnel is fitted with a nitrogen inlet vented through an oil bubbler. The system is placed under a nitrogen atmosphere, magnetic stirring is initiated, and contents of the flask are cooled in an ice-water bath. The contents of the dropping funnel are added to the cooled tartrate during 30 min and the yellow mixture is stirred for an additional 15 min after completion of the addition. The cooling bath is removed and the reaction mixture is allowed to reach 25°C and stir for an additional 10 hr or until disappearance of the tartrate as judged by TLC analysis. The light brown reaction mixture is poured into 500 g of ice, and the resulting mixture is transferred to a 1-L separatory funnel and extracted four times with 80 mL of ether. The combined ether extracts are washed successively three times with 60 mL of water, and then 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator to give a pale yellow oil.

A single-necked, 300-mL, round-bottomed flask, equipped with a Teflon-coated stirring bar and an efficient reflux condenser bearing a drying tube packed with blue indicator silica gel beads, is charged with the yellow oil obtained above and 140 mL of ethanol to which is cautiously added 4 mL of acetyl chloride with stirring. The mixture is heated under gentle reflux for 7 hr, then cooled to room temperature, the condenser is removed, and the mixture is concentrated under reduced pressure at 50–60°C using a rotary evaporator to give a yellow oil. The crude product is transferred to a silica gel column with the aid of a small amount of hexane-ethyl acetate (4:1) and eluted with the same mixed solvent in 60-mL fractions. Fractions 5 to 15 are combined and concentrated on a rotary evaporator to give a colorless oil, which, upon vacuum distillation, affords 24.36–25.73 g (72–76%) of 99% pure (GLC) diethyl (2S,3S)-2-bromo-3-hydroxysuccinate, bp 93–94°C (0.2 mm) [lit.bp 123–125°C (0.6 mm)], [α]^25.6D −16.8° (EtOH, c 5.70), [α]²⁷D −35.72° (neat) [lit.[α]²¹D −28.9° (neat)].

B. Diethyl (2R,3R)-2,3-epoxysuccinate (CAS NO.: )(3). An oven-dried, 300-mL, round-bottomed flask, equipped with a Teflon-coated stirring bar and a rubber septum through which is inserted a large bore, needle-tipped nitrogen line vented through an oil bubbler, is charged with 29.7 g (0.110 mol) of diethyl (2S,3S)-2-bromo-3-hydroxy succinate and 80 mL of dry ethanol. In a separate, oven-dried, 250-mL, round-bottomed flask, capped with a rubber septum and vented though a bubbler as described above, a solution of ethoxide in ethanol is prepared from 3.05 g of sodium (0.132 mol) and 120 mL of dry ethanol. (Caution: This operation should be conducted in a well-ventilated hood. Sodium is a highly reactive metal, avoid exposure to moisture. gas, which is highly flammable and forms explosive mixtures with air, is rapidly evolved. External cooling may be necessary.) The two flasks are placed under a nitrogen atmosphere, and connected by means of a long double needle-tipped cannula. Magnetic stirring is initiated, and the ethanolic solution of the succinate 2 is cooled in an ice-water bath for 15 min followed by dropwise addition of the solution of sodium ethoxide in ethanol which is transferred via the cannula under a very slight positive pressure of nitrogen. Complete transfer of the base should require 2 hr. The reaction mixture is stirred for an additional 20 min at 0–10°C (bath temperature) and then quenched by the addition of 1.43 mL (0.025 mol) of acetic acid. The reaction mixture is diluted with 900 mL of water, transferred to a 2-L separatory funnel, and extracted four times with 100 mL of dichloromethane. The combined organic phases are washed with 100 mL of brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator to give a colorless oil. Vacuum distillation of this crude product affords 17.7–18.7 g (85–90%) of diethyl (2R,3R)-2,3-epoxysuccinate (3), bp 97–98°C (0.9 mm) [lit.bp 100–104°C (4 mm)], [α]²⁵D −110° (EtOH, c 5.09), [α]²⁸D −115° (neat) [lit.[α]^21.5D −88.47° (ether, c 1.030)] which is homogeneous by GLC analysis.

C. Diethyl (2S,3R)-2-azido-3-hydroxysuccinate (CAS NO.:101924-62-3)(4). An oven-dried, 200-mL, round-bottomed flask, containing a Teflon-coated stirring bar, is capped with a septum while hot, and purged with nitrogen until cool via insertion through the septum of a needle-tipped nitrogen line (vented through an oil bubbler) and an open needle. The open needle is removed and the flask is charged with a solution of 3.45 g (0.0282 mol) of 4-(dimethylamino)pyridine (P) in 17 mL of N,N-dimethylformamide (DMF) and 1.93 mL (0.0329 mol) of dry ethanol through the septum via syringe. Stirring is initiated and the mixture is cooled in an ice-water bath. To this cold solution is added 17.1 mL (0.122 mol) of azidotrimethylsilane dropwise at 0°C by means of a syringe. The heterogeneous mixture is stirred for 15 min at room temperature (25°C) and then a solution of 17.7 g (0.0940 mol) of diethyl (2R,3R)-2,3-epoxysuccinate (3) in 50 mL of chloroform, prepared in a septum-capped, oven-dried, 100-mL, round-bottomed flask, is rapidly transferred via cannula with the aid of a positive nitrogen pressure as above (Part B). The mixture is stirred at 25°C until epoxide 3 can no longer be detected upon TLC analysis of the reaction mixture (40 hr). The mixture is then diluted with 300 mL of water, transferred to a 1-L separatory funnel, and the organic phase separated. The aqueous phase is extracted four times with 60 mL of a hexane-ether mixture (1:1 v/v). The combined organic phases are added to 20 mL of a magnetically stirred 2.3 N solution of hydrogen chloride in ethanol, followed by dilution of the resulting mixture with an additional 50 mL of ethanol and continued stirring at room temperature for 30 min. After transfer to a separatory funnel, the solution is washed successively with four 50-mL portions of water, 50 mL of saturated aqueous sodium bicarbonate solution, and 50 mL of saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure using a rotary evaporator followed by exposure to high vacuum affording 18.6 g (86%) of 96–98% pure diethyl (2S,3R)-2-azido-3-hydroxysuccinate (4) as a pale yellow oil, [α]²⁰D +31.8° (EtOH, c 18.1), as judged by NMR analysis. This material contains 2–4% of the inseparable (2R,3R)-diastereomer.

D. Diethyl (2S,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate (CAS NO.: 174682-54-3)(5). A 500-mL, single-necked, round-bottomed flask, equipped with a Teflon-coated stirring bar, is charged with a suspension of 0.91 g of 10% palladium on carbon catalyst in 100 mL of ethyl acetate. The flask is connected to a normal pressure hydrogenation apparatus and the catalyst is saturated with hydrogen. After removal of the hydrogen, a solution of 18.2 g (0.0785 mol) of 4 and 20.6 g (0.0942 mol) di-tert-butyl dicarbonate in 80 mL of ethyl acetate is added to the suspension of catalyst, a hydrogen atmosphere reestablished, and the suspension is stirred at room temperature under a slight positive pressure of hydrogen for 4–6 hr. The suspension is filtered through a Celite pad, and the pad is rinsed with several portions of ethyl acetate. The combined ethyl acetate solutions are concentrated on a rotary evaporator and finally under high vacuum to give a pale yellow oil that is initially purified by means of a column packed with silica gel (100 g) using hexane-ethyl acetate (6:1) as eluent. Fractions containing the product are combined and concentrated on a rotary evaporator to give 23.3 g of crude 5 as a colorless oil. The oily crude 5 is dissolved in 70 mL of hexane-ether (3:1), and the solution is cooled to -30°C, seeded, and kept overnight at that temperature (freezer) to allow crystallization. The mother liquor is siphoned out while the mixture is kept at -30°C (dry ice-acetone bath). The crystals are washed with several portions of hexane-ether (3:1) at -30°C, then dried under high vacuum to provide 12.2–12.7 g of diastereomerically and enantiomerically pure diethyl (2S,3R)-2-(N-tert-butoxycarbonyl)amino-3-hydroxysuccinate (5) as colorless prisms, mp 33–34°C; [α]²⁴D +13.1° (EtOH, c 6.32); [α]²⁴D +28.7° (CHCl₃, c 6.05). The combined mother liquor and the hexane–ether (3:1) washings are concentrated on a rotary evaporator to give a colorless oil, which upon crystallization as above provides an additional 2.7–3.8 g of product 5. The combined yield of crystalline 5 is 15.9–16.5 g (66–73%).

Notice: Parts A and C of this procedure should be carried out in a well-ventilated hood since toxic hydrogen bromide and azidotrimethylsilane are handled and toxic hydrogen azide is liberated during the course of the reaction.