Potassium Phosphate, Tribasic → 5-[(1S,4R,5S,15R)-5-(3,5-difluoro-benzyl)-4-hydroxy-7-oxo-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-19-yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

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Step FF (1): Copper(I) iodide (20 mg, 0.104 mmol), K3PO4 (67 mg, 0.316 mmol), L-proline (9.2 mg, 0.080 mmol), and DMSO (1 mL) were combined in a 1 dram vial. tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (40.7 mg, 0.192 mmol) and (1S,4R,5S,15R)-19-bromo-5-(3,5-difluoro-benzyl)-4-hydroxy-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-7-one (39 mg, 0.073 mmol, TFA salt of Example 68) were added to the mixture. The vial was capped, shaken, and placed into a heating block preheated to 90° C. The reaction was allowed to stir magnetically for 16 h at 90° C. The reaction was cooled to rt, and diluted with water and EtOAc. The mixture was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuo. The crude residue was purified by flash column chromatography on a small pre-packed silica gel column, eluted with 30% EtOAc/hexane, then 5-10% methanol/DCM. The pure fractions were pooled (Rf=0.54 in 5% methanol/DCM) and concentrated in vacuo to afford 30 mg (55% yield) of the title compound as a brown solid/residue. This material was determined to be a mixture of cis and trans isomers by proton NMR. Analytical HPLC conditions (methanol/0.1% TFA water, 4.6×50 mm, 5 micron, Waters X-Bridge C18 column, 5 mL/min, 254 nm wavelength) showed a purity of 90% and a Rt of 4.79 min.

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