1,1-Dimethylethyl N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]carbamate

General procedure: To a colorless solution of 150mg (0.50mmol) of Cbz-L-Phe-OH 3a in 10mL of THF were added 67μL (0.70mmol, 1.4equiv) of ClCOBoc-L-valine (4.00 g, 18.4 mmol, 1.00 equiv) and N-methylmorpholine (2.01 g, 19.9 mmol, 1.08 equiv) were dissolved in 1, 2-dimethoxyethane (94.0 mL) at 0 °C. Then, isobutylchloroformiate (2.72 g, 19.9 mmol, 1.08 equiv) was added dropwise. The reactionmixture was stirred for 15 min at 0 °C. Afterwards, an aqueous ammonia solution (25percent;8.20 mL, 121 mmol, 6.57 equiv) was added dropwise. The temperature was raised to rt whilestirring. After 22.5 h, the reaction was terminated by adding HCl (1.0 M). The aqueous layerwas extracted with EtOAc (4×). The combined organic layers were washed with HCl (0.1 M)and subsequently dried over MgSO4, filtered and concentrated under reduced pressure.Amide 30 (3.91 g, 18.1 mmol, 98percent) was obtained as a colourless solid.a General procedure: To a colorless solution of 150mg (0.50mmol) of Cbz-L-Phe-OH 3a in 10mL of THF were added 67muL (0.70mmol, 1.4equiv) of ClCO2Et and 209muL (1.5mmol, 3.0equiv) of Et3N at 0C. After stirring for 30min at 0C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) were added at 0C to the colorless suspension. The mixture was stirred for 30min at 0C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 129mg (86% yield) of Cbz-L-Phe-NH2 4a. 4.3.11 Boc-l-Val-NH2 4f 106'mg (98%); >99% ee; coloress solid; mp: 149-152'C; [alpha]30D?=?-2.4 (c 1.00, MeOH); 1H NMR (400'MHz, CDCl3): delta 0.94 (d, J?=?6.8'Hz, 3H, CH3CH), 0.99 (d, J?=?6.8'Hz, 3H, CH3CH), 1.45 (s, 9H, (CH3)3C), 2.16 (ddd, J?=?6.7, 6.8, 6.8'Hz, 1H, CH(CH3)2), 3.96 (dd, J?=?6.7, 7.8'Hz, 1H, CHCO), 5.03, 5.42, 5.89 (br, br, br, 1H, 1H, 1H, NH, NH2); 13C NMR (100'MHz, CDCl3): delta 17.8, 19.3, 28.3, 30.8, 59.5, 79.9, 156.0, 174.4; IR (KBr, vmax/cm-1): 3386 (CONH), 3345 (CONH), 3205 (CONH), 1680 (CON), 1641 (CON); HRMS (ESI-TOF): Calcd for C10H20N2O3Na (M+Na)+: 239.1366, found: 239.1340; The enantiomeric ratio was determined by HPLC (Chiralcel OD: hexane/2-propanol?=?95/5): Tr 9.4'min.General procedure: Boc-protected amino acid 10 (2.0 mmol, 1 equiv), EEDQ (1244 mg, 2.2 mmol, 1.1 equiv), and ammonium hydrogencarbonate (474 mg, 6.0 mmol, 3 equiv) were suspended in chloroform (12 mL), and the mixture was stirred overnight at room temperature. Then the mixture was diluted and washed with water, and then evaporated to give a white solid, which was recrystallized and afford compounds 11a-h from ethyl acetate-hexane.General procedure: Isobutyl chloroformate(1.93 mmol, 0.25 mL) and NMM (2.31 mmol, 0.26 mL) were added dropwise to a solution of the Boc-amino acid(200 mg) or Lonidamine (200 mg, 0.62 mmol) in THF(10 mL) stirring at - 20 C for 30 min. NH4OHsolution(2.1 eq., 0.37 mL) was added to the reaction stirring at- 20C for 30min, then the reaction was maintained at r.t.overnight. The reaction mixture was evaporated to drynessand the residue extracted with EtOAc. The organic phasewas washed with 5% citric acid, NaHCO3s.s. and NaCl s.s., dried on Na2SO4anhydrous and evaporated to obtain thedesired amide derivative as a crude white product. This procedurewas also applied to the synthesis of LONI B derivativepreviously characterized in the literature (Angapellyetal. 2017).Boc-Val-OH has been converted to its amide derivative following thegeneral procedure D. The Boc protection has been removedwith a mixture of TFA/DCM = 1:1 at r.t. for 1h, then theintermediate TFA salt was coupled to Lonidamine, followingthe general procedure B.

Molecular Weight:216.28
XLogP3:0.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:216.14739250
Monoisotopic Mass:216.14739250
Topological Polar Surface Area:81.4
Heavy Atom Count:15
Complexity:244
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes