tert-butyl (2S)-2-amino-3-phenylpropanoate

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

Procedure: 834 mg of HBTU and 0.24 ml of N-methylmorpholine were added at 0° C. under argon to a solution of 446 mg of Z-β-Al-a-OH and 785 mg of H-Asp(O-tBu)-Phe-O-tBu (obtained from the condensation of Z-Asp(O-tBu)-OH with H-Phe-O-tBu followed by hydrogenolysis). After 5 hours, the mixture was concentrated and the residue was partitioned in ethyl acetate/5% NaHCO3. The organic phase was washed with water and 1M KHSO4. The organic extracts were dried, filtered and concentrated. The residue was recrystallised from ethyl acetate/diisopropyl ether resulting in 592 mg of Z-β-Ala-Asp(O-tBu)-Phe-O-tBu, m.p. 138°-139° C.

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

Procedure: A mixture of 33 g of benzyl 2-bromo-4-phenylbutyrate, 22.1 g of (L)-phenylalanine tert-butyl ester, 13.8 g of potassium carbonate and 30 ml of hexamethylphosphoric triamide was stirred at room temperature overnight. Then, ethyl acetate was added to the mixture, and the insolubles were removed by filtration. The filtrate was washed and dried, and then the solvent was removed. The residue was purified by silica gel to obtain 16.6 g of N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)-(L)-phenylalanine tert-butyl ester and 9.9 g of N-((1R)-1-benzyloxycarbonyl-3-phenylpropyl)-(L)-phenylalanine tert-butyl ester as oily products, respectively. the insolubles were removed by filtration The filtrate was washed dried the solvent was removed The residue was purified by silica gel

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

Procedure: A mixture of 33 g of benzyl 2-bromo-4-phenylbutyrate, 22.1 g of (L)-phenylalanine tert-butyl ester, 13.8 g of potassium carbonate and 30 ml of hexamethylphosphoric triamide was stirred at room temperature overnight. Then, ethyl acetate was added to the mixture, and the insolubles were removed by filtration. The filtrate was washed and dried, and then the solvent was removed. The residue was purified by silica gel to obtain 16.6 g of N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)-(L)-phenylalanine tert-butyl ester and 9.9 g of N-((1R)-1-benzyloxycarbonyl-3-phenylpropyl)-(L)-phenylalanine tert-butyl ester as oily products, respectively. the insolubles were removed by filtration The filtrate was washed dried the solvent was removed The residue was purified by silica gel

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

Procedure: The benzaldehyde Schiff base of glycine tert-butyl ester (compound 9) (0.44 g; 2 mmol), benzyl bromide (0.32 g; 1.9 mmol), and N-(9-anthracenylmethyl)cinchonidium chloride (compound 10) (107 mg; 0.2 mmol) were added to toluene (4 mL), and the mixture was stirred vigorously (1400 rpm) with ice-salt cooling. When the internal temperature thereof had dropped to −5° C. or less, 48% KOH aqueous solution (0.46 g; 4 mmol, 2 equivalents) was added thereto. The mixture was stirred for one hour while maintaining the internal temperature between −5° C. and −2° C. Distilled water (10 mL) was added thereto and the toluene layer was collected, and then the alkylated Schiff base (compound 11) was extracted with toluene (10 mL×2). Thus obtained toluene layers were combined with the toluene layer collected previously, 1 N hydrochloric acid (10 mL) was added thereto, and the mixture was stirred at room temperature for one hour. The aqueous layer was collected by separation, and then the aqueous layer was washed with toluene (10 mL), and sodium carbonate was added thereto carefully to avoid too vigorous bubbling until pH of the solution reached not lower than 11 (confirmed by universal pH test paper). The mixture was extracted with ethyl acetate (10 mL×3) to collect the ethyl acetate layer. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to give (S)-phenylalanine tert-butyl ester (compound (S)-12) (0.11 g; yield 25%, optical purity 80% ee). The optical purity of the compound 12 was measured by HPLC under the following conditions: When the internal temperature thereof had dropped to −5° C. or less while maintaining the internal temperature between −5° C. and −2° C the toluene layer was collected the alkylated Schiff base (compound 11) was extracted with toluene (10 mL×2) collected previously 1 N hydrochloric acid (10 mL) was added the mixture was stirred at room temperature for one hour The aqueous layer was collected by separation the aqueous layer was washed with toluene (10 mL), and sodium carbonate was added carefully to avoid too vigorous bubbling until pH of the solution The mixture was extracted with ethyl acetate (10 mL×3) to collect the ethyl acetate layer The ethyl acetate layer was dried over magnesium sulfate concentrated under reduced pressure

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

Procedure: In analogy to Example 4, reaction of phenylalanine tert-butyl ester and 3-(4-cyanophenyl)-2-oxo-5-oxazolidinecarboxylic acid [obtainable according to Example 1] gives tert-butyl (2R)-2-[3-(4-cyanophenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionate, m.p. 72°.

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

Procedure: In analogy to Example 4, reaction of phenylalanine tert-butyl ester and 3-(4-cyanophenyl)-2-oxo-5-oxazolidinecarboxylic acid [obtainable according to Example 1] gives tert-butyl (2R)-2-[3-(4-cyanophenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionate, m.p. 72°.

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

Procedure: 1.3 ml of N-ethylmorpholine are added to the solution of 2.65 g of Z-Ile-OH, 2.58 g of H-Phe-OBut and 1.35 g of HOBt in 30 ml of dimethylformamide and 2.2 g of DCC are added to 0° C. The mixture is allowed to stand for 1 hour at 0° C. and overnight at room temperature. On the following day the precipitate is filtered off and the filtrate is concentrated. The residue is partitioned between ethyl acetate and water. The ethyl acetate phase is extracted by shaking with 20 ml of saturated NaHCO3 solution, 20 ml of K2SO4 /KHSO4 solution and 20 ml of NaHCO3 solution and is dried over Na2SO4 and concentrated. The product crystallizes from petroleum ether. Yield 3.7 g, melting point 122°-125°. are added to 0° C On the following day the precipitate is filtered off the filtrate is concentrated The residue is partitioned between ethyl acetate and water The ethyl acetate phase is extracted is dried over Na2SO4 concentrated The product crystallizes from petroleum ether

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

Procedure: A solution of LiOH (400 mg, 16.7 mmol, 2.15 eq) in dry DMF (44 mL) containing activated 4 Å molecular sieves was stirred vigorously for 20 min, treated with Phe-Ot-Bu*HCl (2 g, 7.76 mmol, 1 eq), stirred for 45 min, treated with a solution 80% propargyl bromide (1.4 mL, 9.4 mmol, 1.21 eq) in toluene, stirred for 16 h and filtered through a pad of Celite™, which was washed with EtOAc (Cho, J. H. and B. M. Kim, Tetrahedron Lett. 2002, 43 1273-1276). The filtrate was washed three times with water, dried over MgSO4 and the volatiles were evaporated to provide an oil, which was purified by chromatography on silica gel using 30% EtOAc in hexane as eluent. Evaporation of the collected fractions gave ester 41 as yellow oil (1.66 g, 83%): Rf=0.53 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 2H), 7.24 (m, 3H), 3.62 (t, J=6.9 Hz, 1H), 3.47-3.36 (m, 2H), 2.96 (m, 2H), 2.20 (m, 1H), 1.77 (s, 1H), 1.39 (s, 9H); 13C NMR (300 MHz, CDCl3) δ 172.9, 137, 129.2, 128.1, 126.4, 81.3, 81.0, 71.6, 61.5, 39.4, 36.5, 27.8. IR (thin film) v 3297, 2981, 2942, 1723, 1370, 1152, 700 cm−1; HRMS (LC-ESI) m/z calcd for C16H22NO2 [MH]+ 260.1645. Found 260.1634. stirred for 45 min stirred for 16 h filtered through a pad of Celite™, which was washed with EtOAc (Cho, J. H. and B. M. Kim, Tetrahedron Lett. 2002, 43 1273-1276) The filtrate was washed three times with water dried over MgSO4 the volatiles were evaporated to provide an oil, which was purified by chromatography on silica gel using 30% EtOAc in hexane as eluent Evaporation of the collected fractions

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

Procedure: To a solution of 0.09 g (56.25 mmol) 3-quinuclidinone and 4.15 g (18.75 mmol) Phe-O-t-Bu in 50 ml methanol was added over a 12 hour period a solution of 2.95 g (46.9 mmol) sodium cyanoborohydride in 13 ml methanol. After stirring for an additional 8 hours, 5.78 g (50.0 mmol) pyridine hydrochloride was added and after 11/2 hours stirring, sodium chloride was removed by filtration. The filtrate was concentrated to a foam which was treated with 15 ml methanol and 50 ml ethyl acetate to give a slurry of the byproduct 3-hydroxy quinuclidine hydrochloride (74% of excess) which was removed by filtration. The filtrate was concentrate to an oil and charged with 10 ml methanol to a 5×200 cm column of LH-20 and eluted with methanol. The product fraction contained 6.54 g of a mixture of diastereomers in a 55:45 ratio as established by HPLC. after 11/2 hours stirring sodium chloride was removed by filtration The filtrate was concentrated to a foam which was treated with 15 ml methanol and 50 ml ethyl acetate

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

Procedure: Prepared from Intermediate D and L-phenylalanine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 7.46-7.21 (5H, m), 6.95 (1H, s), 6.34 (1H, s), 4.32-4.09 (3H, m), 3.27-2.88 (6H, m), 1.84-1.63 (5H, m), 1.34 (9H, s), 1.19 (6H, d, J=7.0 Hz). LC/MS: purity 97.5%, m/z 511 [M+H]+

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

Procedure: Prepared from Intermediate D and L-phenylalanine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 7.46-7.21 (5H, m), 6.95 (1H, s), 6.34 (1H, s), 4.32-4.09 (3H, m), 3.27-2.88 (6H, m), 1.84-1.63 (5H, m), 1.34 (9H, s), 1.19 (6H, d, J=7.0 Hz). LC/MS: purity 97.5%, m/z 511 [M+H]+

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

Procedure: 834 mg of HBTU and 0.24 ml of N-methylmorpholine were added at 0° C. under argon to a solution of 446 mg of Z-β-Al-a-OH and 785 mg of H-Asp(O-tBu)-Phe-O-tBu (obtained from the condensation of Z-Asp(O-tBu)-OH with H-Phe-O-tBu followed by hydrogenolysis). After 5 hours, the mixture was concentrated and the residue was partitioned in ethyl acetate/5% NaHCO3. The organic phase was washed with water and 1M KHSO4. The organic extracts were dried, filtered and concentrated. The residue was recrystallised from ethyl acetate/diisopropyl ether resulting in 592 mg of Z-β-Ala-Asp(O-tBu)-Phe-O-tBu, m.p. 138°-139° C.