N-BOC-3-IODO-L-ALANINE BENZYL ESTER

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Onto zinc foil (99.9% Aldrich 35, 602-6,118.5 mg, 1.813 mmol) is cut in small pieces is added DMF (freshly distilled from CaH2 under argon, 0.4 mL) and 1,2-dibromoethane (0.006 mL, 0.065 mmol) under argon. The mixture is heated at 50° C. for 10 min, then allowed to cool and trimethylsilyl chloride (0.003 mL, 0.026 mmol) is added. The reaction is stirred for 25 min and a solution of (R)-2-t-butoxycarbonylamino-3-iodo-propionic acid benzyl ester (Fluka, 342 mg, 0.844 mmol) in DMF (1 mL) is added. After 1 h, the mixture is decanted to a solution of the title C compound, 5-(3-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (300 mg, 0.65 mmol), tri-o-tolylphosphine (29.9 mg, 0.13 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (29.9 mg, 0.033 mmol) in DMF (2 mL). After stirring for 1.5 h, the resulting reaction mixture is poured onto water (100 mL), extracted with EtOAc (2×100 mL). The combined EtOAc layers are washed with water (1×200 mL) and brine (1×200 mL), dried over anhydrous MgSO4, filtered and concentrated to give a yellow oil. This is chromatographed on a 35 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 12:88 over 40 min. Fractions containing product are combined and concentrated to yield (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester as a clear oil: [M+NH4]+=627.0, [M−HCO2]−=654.1. freshly distilled from CaH2 under argon to cool After 1 h After stirring for 1.5 h the resulting reaction mixture is poured onto water (100 mL) extracted with EtOAc (2×100 mL) The combined EtOAc layers are washed with water (1×200 mL) and brine (1×200 mL) dried over anhydrous MgSO4 filtered concentrated to give a yellow oil This is chromatographed on a 35 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 12:88 over 40 min Fractions containing product concentrated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Onto zinc foil (99.9% Aldrich 35, 602-6, 775 mg, 11.85 mmol) cut in small pieces is added DMF (freshly distilled from CaH2 under argon, 4.5 mL) and 1,2-dibromoethane (0.033 mL, 0.38 mmol) under argon. The mixture is heated at 50° C. for 10 min, then allowed to cool and trimethylsilyl chloride (0.19 mL, 0.153 mmol) is added. The reaction is stirred for 25 min and a solution of (R)-2-t-butoxycarbonylamino-3-iodo-propionic acid benzyl ester (Fluka, 2.18 g, 5.37 mmol) in DMF (10 mL) is added. After 15 min, the mixture is decanted into a solution of the title A compound, 5-(4-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.75 g, 3.82 mmol), tri-o-tolylphosphine (232.5 mg, 0.764 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (175 mg, 0.191 mmol) in DMF (13 mL). After stirring for 1.5 h, the resulting reaction mixture is poured onto a mixture of saturated aqueous ammonium chloride (200 mL) and water (200 mL) and extracted with EtOAc (2×250 mL). The organic solution is washed with water (1×200 mL) and brine (1×200 mL), then filtered through celite to removed a strong gray precipitate. The filtrate is dried over anhydrous Na2SO4, filtered and concentrated to give a dark red brown oil. This is chromatographed on a 110 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 10:90 over 25 min. Fractions containing product are combined and concentrated to yield (S)-2-t-butoxycarbonylamino-3-(4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester as a white solid after tritruration with Et2O: [M+NH4]+=627.0, [M−HCO2]−=654.1. freshly distilled from CaH2 under argon to cool After 15 min After stirring for 1.5 h the resulting reaction mixture extracted with EtOAc (2×250 mL) The organic solution is washed with water (1×200 mL) and brine (1×200 mL) filtered through celite to removed a strong gray precipitate The filtrate is dried over anhydrous Na2SO4 filtered concentrated to give a dark red brown oil This is chromatographed on a 110 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 10:90 over 25 min Fractions containing product concentrated