Method for the stereoselective synthesis of cyclic amino acids

[0602]

[0603] (i) NCCH 2 CO 2 Et, NH 4 OAc, AcOH, toluene, reflux;

[0604] (ii) PhCH 2 MgCl, THF, -78°C;

[0605] (iii) KOH, ethylene glycol, 160°C;

[0606] (iv) (S)-(-)-α-methylbenzylamine, EtOAc, 0 °C;

[0607] (v) HCl(aq);

[0608] (vi)(PhO) 2 P(O)N 3 ,Et 3 N, toluene, reflux;

[0609] (vii) MeOH, toluene, reflux;

[0610] (viii)RuCl 3 , NaIO 4 , CCl 4 , MeCN, H 2 O;

[0611] (ix) 6N HCl, 1,4-dioxane.

[0612] (E and Z)-cyano-((R)-3-methyl-1,1-cyclopentylene)-ethyl acetate

[0613] (R)-(+)-3-Methylcyclopentanone (5g, 51.0mmol), ethyl cyanoacetate (5.42mL, 51.0mmol), ammonium acetate (0.4g, 5.1mmol) and glacial acetic acid (0.58 mL, 10.2 mmol) was refluxed in toluene (30 mL) using a Dean-Stark trap. After 6 hours, the mixture was cooled and diluted with ethyl acetate (100 mL), washed with water (3 x 80 mL) and brine then dried (MgSO 4 ). The solvent was evaporated under reduced pressure. The residue was chromatographed (silica gel, heptane / ethyl...

[0653]

[0654]

[0655] (i)(CH 3 ) 3 SiCHN 2 , MeOH, toluene;

[0656] (ii) RuCl 3 , NaIO 4 , CCl 4 , MeCN, H 2 O;

[0657] (iii) (PhO) 2 P(O)N 3 ,Et 3 N, toluene, reflux;

[0658] (iv) MeOH, toluene, reflux;

[0659] (v) 6N HCl, 1,4-dioxane.

[0660] ((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-acetic acid methyl ester

[0661] Trimethylsilyldiazomethane (31.5mL of 2M hexane solution, 63mmol) was added dropwise to the stirred ((1S,3R)-1-benzyl-3-methyl- Cyclopentyl)-acetic acid (10 g, 43 mmol) in toluene (80 mL) and methanol (20 mL) and the mixture was then warmed to room temperature. The mixture was stirred for 1 hour and then the solvent was evaporated under reduced pressure. The residue was added to ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution, dilute hydrochloric acid, dried (MgSO 4 ) and the solvent was evaporated in vacuo to give 10.6 g (100%) of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid methyl ester;

[0662] R...

[0684]

[0685]

[0686] (i)a) Oxalyl chloride, DMF, CH 2 Cl 2 ; b) t-BuOH, (i-Pr) 2 Net, CH 2 Cl 2 ;

[0687] (ii) RuCl 3 , NaIO 4 , CCl 4 , MeCN, H 2 O;

[0688] (iii)(CH 3 ) 3 SiCHN 2 , MeOH, toluene;

[0689] (iv) CF 3 CO 2 H, CH 2 Cl 2 ;

[0690] (v)(PhO) 2 P(O)N 3 ,Et 3 N, toluene, reflux;

[0691] (vi) MeOH, toluene, reflux;

[0692] (vii) 6N HCl, 1,4-dioxane.

[0693] ((1S,3R)-1-Benzyl-3-methyl-cyclopentyl)-tert-butyl acetate

[0694] Oxalyl chloride (4.14 mL, 47 mmol) was added dropwise to a stirred solution of ((1S,3R)-1-benzyl-3-methyl-cyclopentyl)-acetic acid (10 g, 43 mmol) under argon atmosphere at room temperature. in dichloromethane solution. The reaction mixture was cooled to 5°C, dimethylformamide (1 mL) was carefully added, the mixture was allowed to warm to room temperature and stirring was continued for 2 hours. The solvent was evaporated in vacuo and the residue was diluted with dichloromethane (60 mL). To the reaction m...