Reaction Steps
To a round bottom flask at 0° C. was added (2R,5R)-2,5-dibenzyl-N1,N6-bis((4S,7S,10aS)-7-(hydroxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide (24.4 mg, 0.032 mmol), THF (0.15 mL) and followed by KOtBu (1.0M in THF, 0.0715 mL, 0.071 mmol). The reaction was then warmed to rt and stirred for 15 min. Then, iodomethane (18.5 mg, 0.130 mmol) was added. The reaction was stirred at rt for 4 hr. LC/MS showed a mixture of starting material, mono-ether product and desired di-ether product. Another 71 μL of KOtBu solution was added along with another 8 μL of iodomethane. The reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of saturated aqueous NH4Cl. The solution was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified by RP prep-HPLC (Method A). The fraction containing the product was concentrated to give (2R,5R)-2,5-dibenzyl-N1,N6-bis((4S,7S,10aS)-7-(methoxymethyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide (3.0 mg, 0.0037 mmol, 12% yield) of a white solid. Anal. Calcd. for C42H58N4O6S2 m/z 778.5. found: 779.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.25-7.20 (4H, m), 7.18-7.11 (6H, m), 6.97-6.91 (2H, m), 5.28-5.23 (2H, m), 4.96-4.89 (2H, m), 4.71-4.65 (2H, m), 3.73-3.67 (2H, m), 3.41-3.36 (2H, m), 3.35 (6H, s), 3.23-3.15 (2H, m), 2.85-2.78 (2H, m), 2.73-2.64 (4H, m), 2.40-2.31 (2H, m), 2.09-1.95 (4H, m), 1.92-1.77 (4H, m), 1.72-1.62 (4H, m), 1.61-1.53 (4H, m), 1.51-1.44 (2H, m), 1.40-1.31 (2H, m).
