4-Methylmorpholine → tert-butyl (S)-1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate

Participants

Reaction Conditions

Reaction Steps

(1S*,2R*,4R*)-4-azido-2-benzenesulfonylmethyl-cyclohexylamine trifluoroacetate (see 37c) (2.5 g, 6.3 mmol) was dissolved in DMF (15 mL) prior to the addition of BOP reagent (3.4 g) and N-Boc-L-Met-OH (1.9 g). After cooling to 0° C., NMM (2.6 mL) was added. The resulting mixture was warmed to rt and was stirred overnight. The solution was diluted with EtOAc, and was washed successively with brine and sat. NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave tert-butyl (S)-1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (2.8 g) as a mixture of diastereomers. MS found: (M+H)+=526.2. (52b) The above derivative (52a) was dissolved in MeI (30 mL). After stirring overnight at rt, the solution was concentrated and dried. The resulting material was dissolved in DMF (30 mL) prior to the addition of Cs2CO3 (3.5 g). After stirring 3 h, the solution was diluted with EtOAc and was washed with brine. The organic phase was dried (MgSO4), filtered, and concentrated. Flash chromatography (1:2 up to 2:1 EtOAc/hexane) of the resulting residue provided the bottom diastereomer tert-butyl (S)-1-((1S,2R,4R)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (600 mg). MS found: (M+H)+=478.3. (52c) A portion of the above material (52b) (30 mg) was dissolved in MeOH (4 mL) prior to the addition of 10% Pd/C (20 mg). A hydrogen balloon was added and the mixture was stirred. After stirring 2 h, the Pd/C was filtered off and the solvent was concentrated to give tert-butyl (S)-1-((1S,2R,4R)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (29 mg). MS found: (M+H)+=452.2. (52d) The above material (52c) was dissolved in dichloroethane (5 mL) prior to the adddition of glacial acetic acid (0.2 mL), acetone (1.0 mL), and NaBH(OAc)3 (20 mg). After 20 h, MeOH (4 mL) was added prior to the addition of 37% formaldehyde in water (1 mL). After 15 min, NaBH3CN (20 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 dried, filtered, and concentrated to give tert-butyl (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (15 mg). MS found: (M+H)+=508.3. (52e) A portion of above material (52b) (160 mg) was dissolved in CH2Cl2 (3 mL) and cooled to 0° C. prior to the addition of TFA (4 mL). After the reaction was warmed to rt over 1 h, it was concentrated. This material was dissolved in EtOAc (8 mL) prior to the addition of saturated Na2CO3 solution (3 mL). The organic phase was dried (Na2CO3), filtered, and concentrated to afford free base (S)-3-amino-1-((1S,-2R,4R)-4(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (130 mg). MS found: (M+H)+=408.2. (52f) A portion of the above material (52e) (30 mg, 74 μmol), sodium tert-butoxide (14 mg, 140 μmol), and toluene (0.7 mL) were placed in a reaction tube equipped with a stir bar and screw cap. After passing argon through the reaction mixture for 2 min, BINAP (8 mg, 13 μmol), Pd2(dba)3 (4 mg, 4 μmol) and 1-bromonaphthalene (9 μL, 61 μmol) were added sequentially. The mixture was evacuated again with argon, then sealed and heated to 85° C. overnight. After cooling to room temperature, the mixture was diluted with ether, filtered through a pad of diatomaceous earth, and concentrated. The residue was purified by semi-preparative HPLC, then lyophilized to provide the title compound (9.5 mg) as a gray solid and mixture of diastereomers. ESI MS m/z 534 [C31H39N3O3S+H]+.

Provenance & Evidence