3-Amino-L-alaninehydrochloride

2,3-Diaminopropionic acid hydrochloride is a competitive inhibitor of cystathionase (CTH)[1].

(S)-2, 3-Diaminopropanoic acid hydrochloride (1, 50.0 mg, 0.36 mmol) was dissolved in A/, A/-dimethylformamide (2 mL) and water (1 mL). N, N- Diisopropylethylamine (0.37 mL, 2.13 mmol) and 2, 5-dioxopyrrolidin-l-yl 7-fluoro-l- hydroxy-l, 3-dihydrobenzo[c][l, 2]oxaborole-6-carboxylate (2, 0.20 g, 0.71 mmol) were added at room temperature. After stirring for 2 hours, volatiles were evaporated under reduced pressure and the residue was washed with 1 M aqueous hydrochloric acid (3 mL). Precipitate was collected and purified by preparative HPLC (SunFire Prep C18, 5 muiotaeta, 19 x 100 mm, acetonitrile/water 5:95 to 100:0 + 0.1% FA) and freeze-dried to afford (S)-2, 3-bis(7-fluoro-l-hydroxy-l, 3-dihydrobenzo[c][l, 2]oxaborole-6- carboxamido)propanoic acid (3) as a white solid. Yield: 55.0 mg (34%). JH NMR spectrum (300 MHz, DMSO-d6, deltaEta): 12.90 (bs, 1 H); 9.38 (d, J = 8.8 Hz, 2 H); 8.57-8.38 (m, 2 H); 7.88-7.69 (m, 2 H); 7.31 (t, J = 7.4 Hz, 2 H); 5.03 (d, J=4.2 Hz, 4 H); 4.72-4.59 (m, 1 H); 3.82-3.65 (m, 2 H). LC-MS purity: 100% (ELSD). LC-MS Rt (Kinetex C18, 4.6 mm x 50 mm, acetonitrile/water 5:95 to 100:0 + 0.1% FA): 4.22 min. LC-MS m/z: 461.5 (M + H)+.(S)-2, 3-Diaminopropanoic acid hydrochloride (1, 72.0 mg, 0.36 mmol) was dissolved in A/, A/-dimethylformamide (6 ml_) and water (2 ml_). N, N- Diisopropylethylamine (0.54 ml_, 3.07 mmol) and 2, 5-dioxopyrrolidin-l-yl 4-fluoro-l- hydroxy-l, 3-dihydrobenzo[c][l, 2]oxaborole-6-carboxylate (2, 0.30 g, 1.02 mmol) were added at room temperature. After stirring for 2 hours, volatiles were evaporated under reduced pressure and the residue was purified by preparative HPLC (SunFire Prep C18, 5 muiotatauiota, 19 chi 100 mm, acetonitrile/water 5:95 to 100:0 + 0.1% FA) and freeze-dried to afford (S)-2, 3-bis(4-fluoro-l-hydroxy-l, 3-dihydrobenzo[c][l, 2]oxaborole-6- carboxamido)propanoic acid (3) as a white solid. Yield: 95.0 mg (40%). JH NMR spectrum (300 MHz, DMSO-d6, deltaEta): 9.55 (d, J = 6.2 Hz, 2 H); 8.85 (d, J = 7.5 Hz, 1 H); 8.78 (t, J = 5.5 Hz, 1 H); 8.07 (d, J = 16.7 Hz, 2 H); 7.79-7.62 (m, 2 H); 5.13 (d, J = 6.1 Hz, 4 H); 4.75-4.60 (m, 1 H); 3.90-3.64 (m, 2 H). LC-MS purity: 97% (ELSD). LC-MS Rt (Kinetex C18, 4.6 mm x 50 mm, acetonitrile/water 5:95 to 100:0 + 0.1% FA): 3.30 min. LC-MS m/z: 461.4 (M + H)+.Triethylamine (1.65 mL, 11.8 mmol) was added to a mixture of perfluorophenyl 1- hydroxy-l, 3-dihydrobenzo[c] [ l, 2]oxaborole-6-carboxylate (7, 713 mg, 2.07 mmol) and L-2, 3-diaminopropionic acid hydrochloride (8, L-Dap-OHHCI, 139 mg, 0.99 mmol) in A/, /V-dimethylformamide (10.0 mL) and the resulting solution was stirred at room temperature over weekend. The mixture was evaporated to dryness in vacuo, and the resi- due was partitioned between 1 M aqueous solution of hydrochloric acid (25 mL) and ethyl acetate (50 mL). The phases were separated and the organic one was extracted with ethyl acetate (2 x 25 mL). All organic layers was combined, dried over anhydrous sodium sulfate and concentrated in vacuo to approx. 3 mL volume. Cyclohexane (100 mL) was added and the resulting suspension was stirred at room temperature overnight. The precipitate was collected by filtration and dried in vacuo. The precipitate (crude 9, 288 mg) was dissolved in 50% aqueous solution of acetonitrile (4.8 mL) and subjected to purification by preparative LC/MS (SunFire Prep C18 OBD, 5m, 19 x 100 mm, acetoni- trile/water 5:95 to 100: 0 + 0.1% FA). Pure fractions were combined and freeze-dried to give title compound (9) as white powder. Yield : 116 mg (28%). JH NMR spectrum (300 MHz, DMSO-d6, deltaEta) : 12.73 (bs, 1 H); 9.33 (s, 1 H); 9.30 (s, 1 H); 8.76 (d, J = 7.5 Hz, 1 H); 8.70 (t, J = 5.9 Hz, 1 H); 8.25 (d, J = 0.7 Hz, 1 H); 8.20 (d, J = 0.9 Hz, 1 H); 7.96 (dd, J = 8.1 and 1.7 Hz, 1 H); 7.90 (dd, J = 7.9 and 1.7 Hz, 1 H); 7.52 (d, J = 8.8 Hz, 1 H); 7.48 (d, J = 8.3 Hz, 1 H); 5.05 (s, 2 H); 5.03 (s, 2 H); 4.71-4.62 (m, 1 H); 3.81-3.73 (m, 2 H). LC-MS purity: 100% (ELSD, UV 254 nm). LC-MS Rt (Kinetex C18, 4.6 mm x 50 mm, acetonitrile/water 5 :95 to 100 : 0 + 0.1% FA) : 3.56 min. LC-MS m/z: 425.4 (M + H)+Solution of afforded 2, 5-dioxopyrrolidin-l-yl l-hydroxy-4-(trifluoromethyl)-l, 3- dihydrobenzo[c][l, 2]oxaborole-6-carboxylate (2, 515 mg, 1.50 mmol), (S)-2, 3- diaminopropanoic acid hydrochloride (3, 98.0 mg, 0.70 mmol) and N, N- diisopropylethylamine (0.75 mL, 4.20 mmol) in /V, /V-dimethylformamide (15 mL) and water (4 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated, purified by preparative HPLC (SunFire Prep C18, 5 muiotaeta, 19 x 100 mm, acetonitrile/water 5:95 to 100:0 + 0.1% FA) and freeze-dried to afford (S)-2, 3-bis(l- hydroxy-4-(trifluoromethyl)-l, 3-dihydrobenzo[c][l, 2]oxaborole-6- carboxamido)propanoic acid (4) as white solid. Yield: 153 mg (39%). JH NMR spectrum (300 MHz, DMSO-d6, deltaEta): 12.90 (bs, 1 H); 9.62 (d, J = 4.2 Hz, 2 H); 9.10 (d, J = 8.1 Hz, 1 H); 8.99 (t, J = 5.2 Hz, 1 H); 8.50 (d, J = 15.0 Hz, 2 H); 8.25 (d, 3 = 21.1 Hz, 2 H); 5.21 (d, J = 5.5 Hz, 4 H); 4.84-4.63 (m, 1 H); 3.99-3.81 (m, 1 H); 3.79-3.59 (m, 1 H). LC-MS purity: 100% (ELSD). LC-MS Rt (Kinetex C18, 4.6 mm x 50 mm, acetonitrile/water 5:95 to 100:0 + 0.1% FA): 3.70min. LC-MS m/z: 561.5 (M + H)+.Solution of 2, 3, 4, 5, 6-pentafluorophenol (939 mg, 5.10 mmol), 5-fluoro-l- hydroxy-l, 3-dihydrobenzo[c][l, 2]oxaborole-6-carboxylic acid (1, 1.00 g, 5.10 mmol) and Lambda/, Lambda/'-dicyclohexylcarbodiimide (DCC, 1.05 g, 5.10 mmol) in acetonitriie (30 mL) was stirred at ambient temperature overnight. The reaction mixture was filtered, washed with acetonitriie and evaporated. Crude product 2 (618 mg, 1.71 mmol) reacted with 2, 3-diaminopropionic acid hydrochloride (120 mg, 854 muiotaetaomicronIota) in A/, /V-dimethylformamide (12 mL) and water (6 mL) at ambient temperature overnight. Crude product 3 was purified by preparative HPLC (SunFire Prep C18, 5 muiotaeta, 19 x 100 mm, acetonitrile/water 20:80 to 100:0 + 0.1% FA) and freeze-dried to afford (S)-2, 3-bis(5-fluoro-l-hydroxy- l, 3-dihydrobenzo[c][l, 2]oxaborole-6-carboxamido)propanoic acid (3) as a white solid.Yield: 54.0 mg (14%). JH NMR spectrum (300 MHz, DMSO-d6, deltaEta): 12.88 (bs, 1 H); 9.37 (d, J = 5.9 Hz, 2 H); 8.55 (dd, J = 7.3 and 3.4 Hz, 1 H); 8.50-8.38 (m, 1 H); 8.09 (d, J = 7.5 Hz, 1 H); 8.02 (d, J = 7.5 Hz, 1 H); 7.36 (dd, J = 10.8 Hz and 8.3 Hz, 2 H); 5.01 (d, J = 4.2 Hz, 4 H); 4.70-4.59 (m, 1 H); 3.84-3.65 (m, 2 H). LC-MS purity: 100% (ELSD). LC-MS Rt (Kinetex C18, 4.6 mm x 50 mm, acetonitrile/water 20:80 to 100:0 + 0.1% FA): 4.43 min. LC-MS m/z: 461.4 (M + H)+.

Substrate and competitive inhibitor of cystathionase.

Molecular Weight:140.57
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:140.0352552
Monoisotopic Mass:140.0352552
Topological Polar Surface Area:89.3
Heavy Atom Count:8
Complexity:73.3
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes