Enantioselective synthesis of (–)-chloramphenicol via silver-catalysed asymmetric isocyanoacetate aldol reaction† †Electronic supplementary information (ESI) available: Experimental procedures, characterisation data, copies of 1H and 13C NMR spectra, and HPLC traces. See DOI: 10.1039/c5ob02141c Click here for additional data file.

A concise synthesis of (–)-chloramphenicol, based on the catalytic asymmetric aldol reaction between 4-nitrobenzaldehyde and benzhydryl isocyanoacetate, is reported.

. Solvent screening in the isocyanoacetate aldol reaction between 8 and 7a a a 0.25 mmol, 7a; 1.2 equiv, 8. b Isolated yield of trans diastereomer after FCC. c Dr determined by 1

Practical experimental 2.1. General Remarks
Reactions were performed with magnetic stirring under a positive pressure of nitrogen, unless otherwise stated. Chemicals were obtained from commercial suppliers and used as received. Bulk solutions were evaporated under reduced pressure using a Büchi rotary evaporator. All solvents were commercially supplied or dried by filtration through activated alumina (powder ~150 mesh, pore size 58 Å, basic, Sigma-Aldrich) columns. Petrol ether (PE) refers to distilled light petroleum of fraction (30 -40 °C). Flash column chromatography (FCC) was carried out using Merck silica gel 60 (40-63 µm) as stationary phase. 1 All reactions were followed by thin-layer chromatography (TLC) when practical, using Merck Kieselgel 60 F 254 fluorescent treated silica. Visualisation was accomplished under UV light (λ max = 254 nm) and by staining with aqueous potassium permanganate alkaline solution or vanillin staining dip (prepared by adding 2.5 mL of concentrated H 2 SO 4 to a solution of 15 g of vanillin in 250 mL EtOH 95%). Enantiomeric excesses were determined by HPLC analysis on an Agilent 1200 Series instrument using the chiral stationary phase column specified in the individual experiment and by comparing the sample with the appropriate racemic mixture.
High resolution mass spectra (HRMS) were recorded by the University of Oxford mass spectrometry staff on a Bruker MicroTOF mass spectrometer equipped with an ESI source or on a Micromass GCT equipped with an EI source.
Infrared absorption spectra (IR) were recorded on a Bruker Tensor 27 FT-IR spectrometer from a compressed sample of the solid or from a thin film (the sample was dissolved in CHCl 3 or acetone and the solvent evaporated) on a diamond ATR module. Bands (ν max ) are reported in wavenumbers (cm -1 ) and their intensity is indicated as strong (s), medium (m) or weak (w).
Optical rotations were recorded using a Perkin Elmer 341 polarimeter.
[α] D T values, reported in 10 -1 deg cm 2 g -1 , are calculated on the average value of at least six consecutive readings. Concentrations (c) are quoted in g/100 mL with the appropriate number of significant figures; D refers to the D-line of sodium (589 nm); temperatures (T) are given in degrees Celsius (°C).

S5
Melting points (m.p.) were recorded using a Reichert hot-stage microscope apparatus equipped with an analogic thermometer (2 °C graduation marks) or a Leica Galen III hot-stage microscope apparatus with digital thermometer and are reported uncorrected.
Compound names are those generated by Reaxys following the IUPAC nomenclature.
N-formyl glycine was synthesized following literature procedures. 3 Amino phosphine L-1 and L-3 were prepared from cinchonine and cinchonidine respectively following literature procedures. 4 Ligands L-2 and L-4 were prepared in an analogous fashion from quinidine and quinine respectively. 5 Methyl isocyanoacetate (7b) is commercially available.
Scheme S1. Overview of the synthesis of isocyanoacetates 7

Benzyl 2-isocyanoacetate 9 (7c)
POCl 3 (1.33 mL, 14.2 mmol, 1.1 eq) was added dropwise over 5 minutes to a stirred solution of benzyl 2-formamidoaceate (10c, 2.50 g, 12.9 mmol, 1.0 eq) and Et 3 N (6.1 mL, 44 mmol, 3.4 eq) in CH 2 Cl 2 (40 mL) at 0 °C. Upon addition the pale yellow solution turned pink, then orange. After stirring at 0 °C for 1.5 hours, a Na 2 CO 3 aqueous solution (4 g in 20 mL of water) was added, the biphasic reaction mixture was stirred at rt for 5 minutes, water (20 mL) was then added and the phases were separated. The aqueous layer was extracted twice with CH 2 Cl 2 (60 mL), then the combined organic phases were washed with brine, dried over K 2 CO 3 and filtered. Evaporation of solvents afforded a brown oil, which was purified by FCC (PE/AcOEt 3:1). The title compound 7c was obtained as a yellow solid (1.88 g, 83%). Analytical data are in accordance with those previously reported for this compound.

General procedure B for the enantioselective synthesis of oxazolines 6
The desired ligand L (0.0125 mmol, 0.05 eq), Ag 2 O (1.4 mg, 0.00625 mmol, 0.025 eq) and powdered 4Å MS (72 mg per 0.25 mmol of 7) were stirred in AcOEt (15 mL) at rt for 15 minutes. A solution of isocyanoacetate 7 (0.250 mmol, 1.0 eq) in AcOEt (5 mL) was then added. After approximately 5 minutes, a solution of 4-nitrobenzaldehyde (8,42.0 mg, 0.275 mmol, 1.1 eq) in AcOEt (5 mL) was added, then the reaction mixture was stirred at rt until the isocyanoacetate was consumed (as judged by TLC, PE/AcOEt 4:1, revealed with vanillin staining dip). The reaction mixture was quickly filtered through Celite ® eluting with AcOEt. The filtrate was concentrated under reduced pressure and purified by FCC with the eluent indicated for each compound.

Synthesis and characterisation of 5 Diphenylmethyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrophenyl)propanoate (2S,3R)-(5)
A solution of oxazoline (4S,5R)-6f (683 mg, 1.70 mmol, 1.0 eq) in MeOH (12 mL) was cooled to 0 °C. A solution of thionyl chloride (862 µL, 11.9 mmol, 7.0 eq) in MeOH (12 mL) was cooled to 0 o C and then added dropwise to the reaction flask. The resulting mixture was stirred at 0 °C for 1.5 hours, then quenched by addition of solid NaHCO 3 . Volatiles were removed under reduced pressure and the residue was taken up in CH 2 Cl 2 and water. The phases were separated and the aqueous layer was extracted with CH 2 Cl 2 three times. The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and evaporated to obtain a brown oil. Purification of the crude mixture by FCC (PE/AcOEt 3:2 to 1:2) gave the title compound (2S,3R)-5 as a pale yellow solid (499 mg, 75%). Crystallisation was performed as follow. Compound 5 (150.0 mg, 90% ee) was dissolved in toluene (1 mL) at 100 °C, then slowly allowed to cool down to rt. The resulting solution was left for 16 h at 0 °C, then for 4 days at -20 °C, during which a white solid formed. Toluene was removed with a pipette, then the solid was washed with toluene at rt (3 × 1 mL), each time decanting the solvent off. The solid was then dried (92.0 mg, 61% crystallisation yield, 98% ee). [α] D 20 : +22 (c 0.20, AcOEt, sample with 89% ee).