Dimethyl Sulfoxide → tert-Butyl amino(oxo)acetate

Participants

Reaction Steps

A solution of trans 3-hydroxy-4-azidotetrahydropyran prepared by the procedure of Crotti et al. (Tetrahedron 1994, 50, 1261-1274). (7.0 g, 48.9 mmol) and t-butyldicarbonate (11.2 g, 51.3 mmol) in 90 mL of MeOH was placed in a Parr bottle with 20% Pd(OH)2 (1.4 g) and hydrogenated under 50 psi of overnight. The reaction mixture was filtered through Celite in a sintered glass funnel and concentrated on a rotary evaporator. The residue was triturated in ether and solid was collected and dried to give 6.67 g (63% yield) of Boc-amino alcohol 22a. (22b) DMSO (6.3 mL, 88 mmol) was added dropwise to a 2M solution of oxalyl chloride in CH2Cl2 (24.3 mL, 48.6 mmol) at −78° C. After 15 min, amino alcohol 22a (9.6 g, 44 mmol) in 80 mL CH2Cl2/THF (1:1) was added dropwise followed by dropwise addition of triethylamine (30.8 mL, 220 mmol) The reaction mixture was warmed to rt and stirred for 2. The reaction mixture was partitioned between EtOAc and sat KH2PO4, separated, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated by rotary evaporator. The residue was purified by silica gel chromatography to give 8.0 g (85% yield) of Boc-amino ketone 22b. (22c) Ketone 22b (6.64 g, 30.8 mmol) was dissolved in 66 mL 1:1 EtOH/water and treated with ammonium carbonate (23.7 g, 247 mmol) and potassium cyanide (2.41 g, 36.7 mmol). The reaction was heated in a 65° C. oil bath for 24 hr. The EtOH was removed by rotary evaporator, the residue was extracted from dil. HCl with 3×EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated by rotary evaporator. The residue was triturated in EtOAc at 60° C. and the solid was collected by filtration to give 6.63 g of hydantoin 22c-1 as a single diastereomer (75% yield). The filtrate was concentrated by rotary evaporator to give 3.11 g of hydantion 22c-2 as a 3:2 mixture of diastereomers. MS found: (M+H)−=284. (22d) Compound 22c-2 (3.11 g, 10.9 mmol) was stirred for 1 hr in TFA/CH2Cl2 (1:1, 30 mL) and concentrated on a rotary evaporator to give 4.46 g (100% yield) of the amine 22d (3:2 mixture of diastereomers) which was used for preparation of other analogues. (22e) Compound 22c-1 (1.48 g, 10.9 mmol) was stirred for 1 hr in TFA/CH2Cl2 (1:1, 12 mL) and concentrated on a rotary evaporator to give 1.55 g (100% yield) of the amine 22e (single diastereomer) which was taken to the next step without purification. (22f) A solution of 22e (70 mg, 0.23 mmol) was dissolved in 1 mL DMSO and 1 mL EtOAc and treated with diisopropylethylamine (0.2 mL, 1.15 mmol), BOP (104 mg, 0.23 mmol), 4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (69 mg, 0.23 mmol). The reaction was stirred overnight and then extracted from sat KH2PO4 with EtOAc×3. The combined organic extracts were dried over MgSO4, filtered, concentrated on a rotary evaporator and purified by reverse-phase HPLC to give 28 mg of the product as a TFA salt (21% yield). MS found: (M+H)+=461.

Provenance & Evidence