(2S)-3-methyl-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]butanoic acid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 20.0 g Boc-MeVal-OH (86.5 mmol; Fluka) were dissolved in 80 ml THF and cooled to 0° C. 130 ml 1M BH3-THF (0.13 mol; Fluka) were added at 0° C. over 1 h and the clear, colo reaction mixture was warmed up and stirred at RT for 1 h. The reaction mixture was again cooled to 0° C., 75 ml deionized water were carefully added at 0-5° C. over 0.5 h and after warming up to RT stirring was continued for 1 h. To the colorless solution were added 150 ml 10% Na2CO3 all at once and after stirring for 1 h the reaction mixture was extracted with 600 ml and 300 ml ethyl acetate. The organic layers were washed with brine and dried (Na2SO4). Removal of the solvent by rotary evaporation gave 17.4 g (94%) product as colorless oil. 1H-NMR: the clear, colo reaction mixture was warmed up The reaction mixture was again cooled to 0° C. were carefully added at 0-5° C. over 0.5 h after warming up to RT stirring was continued for 1 h after stirring for 1 h the reaction mixture was extracted with 600 ml and 300 ml ethyl acetate The organic layers were washed with brine dried (Na2SO4) Removal of the solvent by rotary evaporation

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

Procedure: Using General Procedure I Method A, (2S)-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (0.37 g, 1.6 mmol) is coupled to L-proline methyl ester hydrochloride (0.26 g, 1.6 mmol) to give 1-[2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid methyl ester (0.51 g, 93%) as a white solid.

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

Procedure: Using General Procedure I Method A, (2S)-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (0.37 g, 1.6 mmol) is coupled to L-proline methyl ester hydrochloride (0.26 g, 1.6 mmol) to give 1-[2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid methyl ester (0.51 g, 93%) as a white solid.

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

Procedure: Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyric acid to yield (3aR,4S,7aR)-4-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyryloxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-4-((S)-3-methyl-2-methylamino-butyryloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=5.490 min; HPLC Method I

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

Procedure: A solution of 1d (1.08 g, 2.5 mmol) in dichloromethane (35 mL) was stirred at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (682 mg, 0.55 mL, 3.1 mmol) was added and the reaction mixture was stirred at 0° C. for 45 min. N,N-diisopropylethylamine (1.29 g, 1.73 mL, 10 mmol) was added and the solvent was evaporated to afford crude (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (2.5 mmol), which was used in the next step. A solution of crude (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (2.5 mmol) in acetonitrile (30 mL) was stirred at 0° C. under nitrogen. (S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (635 mg, 2.75 mmol, obtained from Sigma-Aldrich Inc.) and N,N-diisopropylethylamine (1.29 g, 1.7 mL, 10 mmol) was added followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.33 g, 3.5 mmol) and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, hydrochloric acid (2 M), water, saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 0:1 to afford the title compound (756 mg, 55%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.88 (d, J=6.5 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H), 1.28 (d, J=6.7 Hz, 3H), 1.49-1.54 (m, 9H), 1.65-2.30 (m, 5H), 2.82 (s, 3H), 2.82-2.94 (m, 1H), 3.62-4.18 (m, 3H), 4.30-4.45 (m, 1H), 4.73 (d, J=12.0 Hz, 1H), 4.95 (d, J=12.0 Hz, 1H), 5.29-5.39 (m, 1H), 6.62-6.77 (m, 1H). LCMS (m/z) 545.2/547.1 [M+H], Tr=3.02 min. The solvent was evaporated the residue was dissolved in ethyl acetate The solution was washed with water, hydrochloric acid (2 M), water, saturated sodium hydrogen carbonate solution, water and brine dried over anhydrous sodium sulfate filtered evaporated The residue was purified by silica gel chromatography

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

Procedure: To a cold (0° C.) solution of N-Boc-N-methylvaline (11) (5.0 g, 21.6 mmol), N,O-dimethylhydroxylamine hydrochloride (2.8 g, 28 mmol), and PyBOP® (11.2 g, 22 mmol) in CH2Cl2 (22 mL) was added DIEA (8.4 mL, 75 mmol). After 1 min., the reaction mixture was warmed to room temperature and stirring was continued for 1 h. If the pH value of the mixture was less than 7, the mixture could be treated with a few drops DIEA to allow the reaction to go to completion. The mixture was poured into 200 mL of diethyl ether and the resultant mixture was washed successively with 3 N hydrochloric acid (3×30 mL), saturated aqueous sodium hydrogen carbonate solution (3×30 mL), and saturated aqueous sodium chloride (3×30 mL). The organic layer was dried with magnesium sulfate and the solvent was evaporated, followed by chromatography of the crude product (silica gel, 1:3 diethyl ether-pet. ether), afforded 12 (4.46 g, 75% yield) as a colourless oil. 1H-NMR (200 MHz, CDCl3): 0.84 (d, J=6.6 Hz, 4H, (CH3)2), 0.85 (d, J=6.6 Hz, 2H, (CH3)2), 1.41 (s, 6H, Boc-(CH3)3), 1.44 (s, 3H, Boc-(CH3)3), 2.15-2.30 (m, 1H, CH), 2.75 (s, 1H, NCH3), 2.78 (s, 2H, NCH3), 3.10 (bs, 3H, NCH3), 3.64 (s, 1H, OCH3), 3.68 (s, 2H, OCH3), 4.66 (d, J=10 Hz, 0.4H, CH), 4.95 (d, J=10 Hz, 0.6H, CH); Exact mass calc'd for C13H27N2O4 (M+H)+: 275.19708. Found (DCI): 275.19710. Optical rotation obtained was [α]25 +128.3 (c 2.9, CHCl3). was continued for 1 h the reaction the resultant mixture was washed successively with 3 N hydrochloric acid (3×30 mL), saturated aqueous sodium hydrogen carbonate solution (3×30 mL), and saturated aqueous sodium chloride (3×30 mL) The organic layer was dried with magnesium sulfate the solvent was evaporated

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

Procedure: To a solution of 2-(3-tert-butyl-4-hydroxylphenyl)-1-(thiazol-2-yl)ethylamine (4.67 g, 16.64 mmol), Boc-N-Me-Val-OH (5.0 g, 21.63 mmol) and CMPI (5.53 g, 21.63 mmol) in THF (110 ml), TEA (5.33 ml, 38.27 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methanol:aqueous ammonia:methylene chloride=3:0.1:100), giving the titled compound (8.10 g, 100%). under cooling with ice extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate evaporated to remove the solvent under reduced pressure

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

Procedure: Using General Procedure I Method A, (2S)-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (0.37 g, 1.6 mmol) is coupled to L-proline methyl ester hydrochloride (0.26 g, 1.6 mmol) to give 1-[2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid methyl ester (0.51 g, 93%) as a white solid.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 20.0 g Boc-MeVal-OH (86.5 mmol; Fluka) were dissolved in 80 ml THF and cooled to 0° C. 130 ml 1M BH3-THF (0.13 mol; Fluka) were added at 0° C. over 1 h and the clear, colo reaction mixture was warmed up and stirred at RT for 1 h. The reaction mixture was again cooled to 0° C., 75 ml deionized water were carefully added at 0-5° C. over 0.5 h and after warming up to RT stirring was continued for 1 h. To the colorless solution were added 150 ml 10% Na2CO3 all at once and after stirring for 1 h the reaction mixture was extracted with 600 ml and 300 ml ethyl acetate. The organic layers were washed with brine and dried (Na2SO4). Removal of the solvent by rotary evaporation gave 17.4 g (94%) product as colorless oil. 1H-NMR: the clear, colo reaction mixture was warmed up The reaction mixture was again cooled to 0° C. were carefully added at 0-5° C. over 0.5 h after warming up to RT stirring was continued for 1 h after stirring for 1 h the reaction mixture was extracted with 600 ml and 300 ml ethyl acetate The organic layers were washed with brine dried (Na2SO4) Removal of the solvent by rotary evaporation

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

Procedure: Using General Procedure I Method A, (2S)-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (0.37 g, 1.6 mmol) is coupled to L-proline methyl ester hydrochloride (0.26 g, 1.6 mmol) to give 1-[2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid methyl ester (0.51 g, 93%) as a white solid.