5-Octyl-α-ketoglutarate synthesis

Yield:1616344-00-3 99%

Reaction Conditions:

with 5%-palladium/activated carbon;hydrogen in ethyl acetate; for 0.25 h;

Steps:

Synthesis of 5-octyl a-KG.

1-Benzyl 5-octyl 2-oxopentanedioate was obtained as follows. To a solution of 5-octyl L-glutamate (0.249 g) in H2O (6.0 ml) and acetic acid (2.0 ml) cooled to 0 °C was added slowly a solution of aqueous sodium nitrite (0.207 g, 3.0 mmol in 4 ml H2O). The reaction mixture was allowed to warm slowlyto room temperature and was stirred overnight. The mixture was concentrated. The resulting residue was dissolved in DMF(10 ml) and NaHCO3 (0.42 g, 5.0 mmol) and benzyl bromide (0.242 ml, 2.0 mmol) were added to the mixture. The mixture was stirred at 21 °C overnight and then extracted with ethyl acetate (3330ml). The combined organic phase was washed with water and brine and dried over anhydrous MgSO4. Flash column chromatography on silica gel eluting with 7/1 hexanes/ethyl acetate gave the mixed diester 1-benzyl 5-octyl (S)-2-hydroxypentanedioate as a colourless oil. To this oil, dissolved in dichloromethane (10.0 ml), were added NaHCO3 (0.42 g, 5.0mmol) and Dess-Martin periodinane (0.509 g, 1.2mmol), and the mixture was stirred at room temperature for 1 h and then extracted with ethylacetate (3330 ml). The combined organic phase was washed with water and brine and dried over anhydrous MgSO4. Flash column chromatography on silica gel eluting with 5/1 hexanes/ethyl acetate gave the desired 1-benzyl 5-octyl 2-oxopentanedioate (0.22 g, 66%) as a white solid. 1H NMR (500MHz, CDCl3): d 7.38 (m, 5H), 5.27(s, 2H), 4.05 (t, J56.5 Hz, 2H), 3.14 (t, J56.5 Hz, 2H), 2.64 (t, J56.5 Hz, 2H),1.59 (m, 2H), 1.28 (m, 10H), 0.87 (t, J57.0 Hz, 3H). 13CNMR (125MHz,CDCl3):d 192.2, 171.9, 160.1, 134.3, 128.7, 128.6, 128.5, 67.9, 65.0, 34.2, 31.7, 29.07, 29.05,28.4, 27.5, 25.7, 22.5, 14.0. 5-Octyl a-KG (5-(octyloxy)-2,5-dioxopentanoic acid) was obtained as follows. To a solution of 1-benzyl 5-octyl 2-oxopentanedioate (0.12 g, 0.344mmol) in ethyl acetate (15 ml) was added 5% Pd/C (80 mg). Over the mixture was passed a stream of argon and then the argon was replaced with hydrogen gas and the mixture was stirred vigorously for 15 min. The mixture was filtered through a thick pad of Celiteto give the desired product 5-octyl a-KG (0.088 g, 99%) as white solid. 1H NMR (500MHz, CDCl3): d 8.16 (br s, 1H), 4.06 (t, J56.5 Hz, 2H), 3.18 (t, J56.5 Hz,2H), 2.69 (t, J56.0 Hz, 2H), 1.59 (m, 2H), 1.26 (m, 10H), 0.85 (t, J57.0 Hz, 3H).13C NMR (125MHz, CDCl3): d 193.8, 172.7, 160.5, 65.5, 33.0, 31.7, 29.08, 29.06,28.4, 27.8, 25.8, 22.5, 14.0.

References:

Chin, Randall M.;Fu, Xudong;Pai, Melody Y.;Vergnes, Laurent;Hwang, Heejun;Deng, Gang;Diep, Simon;Lomenick, Brett;Meli, Vijaykumar S.;Monsalve, Gabriela C.;Hu, Eileen;Whelan, Stephen A.;Wang, Jennifer X.;Jung, Gwanghyun;Solis, Gregory M.;Fazlollahi, Farbod;Kaweeteerawat, Chitrada;Quach, Austin;Nili, Mahta;Krall, Abby S.;Godwin, Hilary A.;Chang, Helena R.;Faull, Kym F.;Guo, Feng;Jiang, Meisheng;Trauger, Sunia A.;Saghatelian, Alan;Braas, Daniel;Christofk, Heather R.;Clarke, Catherine F.;Teitell, Michael A.;Petrascheck, Michael;Reue, Karen;Jung, Michael E.;Frand, Alison R.;Huang, Jing [Nature,2014,vol. 510,# 7505,p. 397 - 401]