4-AMINO-1-BOC-PIPERIDINE-4-CARBOXYLIC ACID

White Powder

A 50 mL flask was charged with amino acid (1.0 g, 4.1 mmol), maleic anhydride (401 mg, 4.1 mmol), and AcOH (15 mL). The mixture was heated at 40 °C for 15 minutes then the reaction was stirred at RT for 2 h. The solvent was removed in vacuo and the residue was dissolved in 10 mL DCM. Hexane was added portion-wise (1 mL portions, 13 mL total) until the product began to crash out. The flask was placed in a -20 °C freezer overnight and filtered. The precipitate was dried in a vacuum desiccator to afford 800 mg (57percent yield) of the title compound. Analytical UPLC-MS: tR = 0.96 min, m/z (ES+) calculated 365.13 (M+Na)+, found 365.19.To a solution of 13 (0.100 g, 0.12 mmol, 1.0 equiv) in dioxane (2 mL), excess HCI (0.1 mL, 4.0 M in dioxane) was added and the resulting solution was stirred for 24 hours. Upon completion, the dioxane was removed and the crude material was re-suspended in methanol and an excess of K2C03 was added (?100 mg). The slurry was stirred at room temperature for 1 hour to ensure basification. K2C03 was filtered off, and the solution was concentrated and purified by flash column chromatography (silica gel, 20percent MeOH in CH2CI2) to afford S2. A portion of this material (0.025 g, 0.032 mmol, 1.0 equiv) was added to a pre-stirred (0°C, 30 minutes) solution of HBTU (0.014 g, 0.05 mmol, 1.5 equiv), 4-amino-i -(tertbutoxycarbonyl)piperidine-4-carboxylic acid (0.012 g, 0.05 mmol, 1.5 equiv) and EDIPA (0.01 mL, 0.05 mmol, 2.0 equiv)) in DMF (2 mL) and stirred for an additional 6 h at 25°C. Upon completion, the reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried (Na2SO4), concentrated, and purified by flash column chromatography (silica gel, 20percent MeOH in CH2CI2) to afford S3. A portion of this slightly impure material (0.020 g) was dissolved in dioxane (1 mL) and HCI (0.1 mL, 4.0 M in dioxane) was added. The resulting mixture was stirred for 6 h at 25°C. After removal of dioxane, the residue was re-suspended infiltered off, and the solution was concentrated and purified by preparative TLC (20percent MeOH in DCM) to afford O4SBTO4 (0.010 g). O4SBTO4: 1H NMR (400 MHz, MeOD) O 7.76 (s, 1 H), 7.58 (s, 1 H), 7.52-7.17 (m, 13 H), 7.08 (t, J = 7.2 Hz, 1 H), 6.92 (t, J = 7.2 Hz, 1 H), 6.72 (m, 2 H), 4.46 (m, 3 H), 4.29 (m, 5 H), 3.77 (m, 3 H), 2.62 (br s, 4 H), 2.45 (br s, 4 H), 2.11 (m, 2 H), 1.48 (m, 1 H). (FIGs. 6 and 8)Step A: l', 4'-Dihydro-3'H-spirofpiperidine-4, 2'-quinoxalin1-3'-one A suspension of 2-bromoaniline (172 mg, 1.0 mmol), 4-amino-l-(iert- butoxycarbonyl)piperidine-4-carboxylic acid (488 mg, 2.0 mmol), cesium carbonate (489 mg, 2.0 mmol) and Cul (19 mg, 0.1 mmol) in DMSO (1 mL) was deoxygenated with nitrogen gas. The reaction mixture was stirred at 125 °C under nitrogen for 5 h, then cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water, then brine, then dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was dissolved in TFA (5 mL) and the solution was stirred at ambient temperature for 2 h, and then concentrated under reduced pressure. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound. MS: m/z = 218.2 ( + 1).

Cyclic α,α-disubstituted amino acid for the preparation of water-soluble highly helical peptides.

Molecular Weight:244.29
XLogP3:-2.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:244.14230712
Monoisotopic Mass:244.14230712
Topological Polar Surface Area:92.9
Heavy Atom Count:17
Complexity:314
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes