Reaction #1479048
ord-e7dd11f9ae614f62ade487248f2c4904
Reaction equation
Reactants
Reagents
Conditions
Workup
- 1workup.WAITAfter 60 min
- 2workup.ADDITIONcontaining ice
- 3WashThe organic layer was washed with water and brine before it
- 4Otherwas dried
- 5Concentrationconcentrated
- 6FiltrationThis crude was filtered through a plug of silica
Procedure
1,4-Cyclohexanedione mono-ethylene ketal (25 g) was dissolved in THF and cooled to −78° C. 1M Lithium bis(trimethylsily)amide (160 mL) in THF was added dropwise. After 30 min, ethyl cyanoformate (15.9 mL) was added dropwise. After 60 min, the solution was poured into EtOAc and water containing ice. The organic layer was washed with water and brine before it was dried and concentrated. This crude was filtered through a plug of silica to give the 8-oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylic acid ethyl ester (32.4 g). MS found: (M+H)+=228.9 (3b) The above derivative (3a)(36.5 g) was dissolved in toluene (500 mL) prior to the addition of (S)-methylbenzyl amine (23 mL) and ytterbium (III) triflate (0.37 g). This miture was stirred at reflux for 3 h. After cooling to rt overnight, the solvent was removed to a golden oil. This oil was dissolved in acetonitrile (420 ml) prior to the addition of acetic acid (100 mL) and NaBH(OAc)3 (67.8 g). The mixture was stirred for 5 days at rt. The solvent was removed before being redissolved in CH2Cl2. After cooling in an ice bath, 1N NaOH was added (pH=8). The organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave 8(S)-(1(S)-phenyl-ethylamino)-1,4-dioxa-spiro[4.5]decane-7(R)-carboxylic acid ethyl ester (26.2 g): 1H NMR (CDCl3, δ ppm, 300 mHz) 1.31 (m, 6H), 1.46 (m, 1H), 1.6-1.84 (m, 4H), 2.1 (t, 1H), 2.85 (m, 1H), 3.16 (m, 1H), 3.76 (m, 1H), 3.93 (m, 4H), 4.19 (q, 2H), 7.2-7.4 (m, 5H) (3c) The above derivative (3b) (16.3 g) was dissolved in Et2O (160 mL) and cooled to 0° C. 1M Lithium aluminum hydride in THF (117.3 mL) was added dropwise. After the addition, the solution was stirred for 2 hr at 0° C. The reaction was quenched with water (4.4 mL) and then 1N NaOH (17.6 mL). The solids were filtered off through a pad of celite. The filtrate was concentrated to an oil. This material was dissolved in MeOH (20 mL) prior to the addition of 20% Pd(OH)2 (3 g). This solution was placed on a Parr aparatus at 50 psi. The solution was mixed overnight. The palladium was filtered off and the solution was concentrated. The resulting oil was dissolved in THF (160 mL) and water (20 mL) prior to the addition of triethylamine (8.8 mL). After cooling to 0° C., dibenzyl dicarbonate (18.2 g) was added. The solution was warmed to rt and was stirred overnight. Ethyl acetate was added along with brine. The organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (7R,8S)-(7-hydroxymethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamic acid benzyl ester (9.8 g). MS found: (M+H)+=322.2. (3d) A portion (100 mg) of the above derivative (3c) was dissolved in THF (10 mL) prior to the addition of tri-n-butylphosphine (0.86 mL). 4-Bromophenyl disulfide (233 mg) was added and the solution was stirred in a 75° C. oil bath. After 5 h, the reaction was cooled to rt and flash chromatography gave (7R,8S)-[7-(4-bromo-phenylsulfanylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester (137 mg). 1H NMR (CDCl3, δ ppm, 300 mHz) 1.39 (t, 1H), 1.5-1.9 (m, 9H), 2.05 (m, 1H), 2.73 (m, 1H), 3.0 (dd, 1H), 3.93 (m, 4H), 4.08 (m, 1H), 4.9 (br d, 1H), 5.1 (s, 2H), 7.17 (d, 2H), 7.36 (m, 7H). (3e) A portion (2.5 g) of the above derivative (3d) was dissolved in CH2Cl2 (100 mL) and cooled to 0° C. prior to the addition 65% M-CPBA (3.1 g). After 2 h, the solution was washed with saturated NaHCO3 solution, brine solution, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (7R,8S)-[7-(4-bromo-benzenesulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester (2.59 g). MS found: (M+H)+=525.9. (3f) A portion (2.1 g) of the above derivative (3e) was dissolved in DMF (10 mL) prior to the addition of PdCl2(PPh3)2 (56 mg) and Sn(Me)4 (0.8 mL). The resulting solution was heated in an oil bath at 80° C. Four addition portions of Sn(Me)4 (0.8 mL each) were added over 3 days. After cooling, EtOAc and brine were added. The organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (7R, 8S)-([7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester (1.0 g). MS found: (M+H)+=460.3. (3 g) A portion (1.0 g) of the above derivative (3f) was dissolved in MeOH prior to the addition of 10% Pd/C (120 mg). A hydrogen balloon was added and the mixture was stirred for 1.5 h. The Pd/C was filtered off and the solvent was concentrated to (7R,8S)-7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-ylamine (740 mg). MS found: (M+H)+=326.3. (3 h) A portion (730 mg) of the above derivative (3 g) was dissolved in DMF prior to the addition of 4-methylmorpholine (0.74 mL) and N-Cbz-L-Met-OH (889.8 mg). After cooling to 0° C., BOP Reagent (1.4 g) was added. The resulting mixture was warmed to rt and was stirred overnight. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl (aq), NaHCO3 solution (aq), and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave {(1S)3-methylsulfanyl-1-[(7R,8S)-7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-ylcarbamoyl]-propyl}-carbamic acid benzyl ester (1.1 g). MS found: (M+Na)+=613.4. (3i) A portion (330 mg) of the above derivative (3 h) was dissolved in MeI (6 mL). After stirring overnight at rt, the solution was concentrated and dried. A portion (50 mg) of the resulting material was dissolved in DMF (1.5 mL) prior to the addition of Cs2CO3 (133 mg). After stirring overnight at rt, EtOAc and brine were added. The EtOAc layer was washed with brine, dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave {(3S)-2-oxo-1-[(7R,8S)-7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-pyrrolidin-3-yl)-carbamic acid benzyl ester (19 mg). MS found: (M+Na)+=565.3. (3j) A portion (580 mg) of the above derivative (3i) was dissolved in CH3CN (10 mL) prior to the addition of 1N HCl (10 mL). The mixture was stirred in a 60° C. oil bath for 4 h. After cooling the solution was concentrated. Flash chromatography of the resulting residue gave {(3S)-2-oxo-1-[(1S,2R)-4-oxo-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-pyrrolidin-3-yl}-carbamic acid benzyl ester (270 mg). MS found: (M+Na)+=521.2. (3 k) The above derivative (3j) (270 mg) was dissolved in Ti(OiPr)4 (4 mL) prior to the addition of isopropylamine (0.4 mL). After 1.5 h, MeOH (7 mL) was added followed by NaBH4 (57 mg). After 1 h, the reaction was quenched by the addition of 0.1N NaOH and filtered through celite. The filtrate was concentrated to a mixture of diastereomers. Flash chromatography of the resulting mixture gave two diastereomers: ({(3S)-1-[(1S,2R,4R)-isopropylamino-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester (3 ka) (59 mg), MS found: (M+H)+=542.3; and ({(3S)-1-[(1S,2R,4S)-isopropylamino-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester (3 kb) (28 mg), MS found: (M+H)+=542.4. (3l) The above derivative (3 ka) (57 mg) was dissolved in MeOH (1.3 mL) prior to the addition of 37% formaldehyde in water (53 mg). After 1.5 h, NaBH3CN (10.4 mg) was added. After 1 h, saturated NaHCO3 was added and some of the MeOH was removed. EtOAc was added and the organic layer was washed with brine, dried, filtered, and concentrated. The resulting residue was dissolved in MeOH prior to the addition of 5% Pd/BaSO4 (100 mg). A hydrogen balloon was added and the mixture was stirred. Two more portions (50 mg each) of 5% Pd/BaSO4 were added. The reaction was stirred for a total of 8 h. The Pd/BaSO4 was filtered off and the solvent was concentrated. The resulting residue was dissolved in DMF prior to the addition of 4-methylmorpholine (34 mg) and 3-trifluoromethyl-benzoic acid (32 mg). After cooling to 0° C., HATU (64 mg) was added. The resulting mixture was warmed to rt and was stirred overnight. EtOAc was added along with saturated NaHCO3 solution. The EtOAc layer was washed with NaHCO3 solution (aq), dried (MgSO4), filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (36 mg). MS found: (M+H)+=594.3.