(S,E)-2-(1-(tert-butoxycarbonyl)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-2-yl)acetic acid (300 mg, 0.60 mmol) can be dissolved in DMF (0.25M). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9 mmol), and 4-Dimethylaminopyridine (0.3 mmol) may be added respectively at room temperature under nitrogen. After about fifteen minutes R-(−)-2-Methyl-2,4-pentanediol (0.60 mmol) may be added and the mixture heated to about 50° C. under nitrogen. The product can be worked up as usual and purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate as a white foam. The (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(2-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-oxoethyl)piperazine-1-carboxylate may be dissolved in anhydrous THF and cooled in a dry ice acetone bath under nitrogen. A 2.0M solution of Butyl lithium in cyclohexane (about 1 mole equivalent) may be added dropwise under nitrogen. After about 15 minutes, iodomethane (about 1 mole equivalent) may be added dropwise under nitrogen. After about one hour, a 2.0M solution of Butyl lithium in cyclohexane (about 1 equivalent) may be added dropwise under nitrogen. After about 15 minutes, iodomethane (about 1 equivalent) may be added dropwise under nitrogen. After about one hour the solution may be concentrated under vacuum to give (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(1-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate as a white foam. The (S)-tert-butyl 4-((E)-8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-2-(1-((R)-4-hydroxy-4-methylpentan-2-yloxy)-2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate may be dissolved in dichloromethane (about 1.1 ml) and cooled in an ice bath. Trifluoroacetic acid (about 0.5 ml) may be added dropwise under nitrogen and slowly allowed to reach room temperature while running overnight. The mixture may be concentrated under vacuum and purified by flash chromatography using 10% Acetone/Dichloromethane as the eluent to give Compound EK.
