碳二亚胺类缩合剂制备酰胺！

To a solution of compound  11  (4.06 g, 10 mmol) in DMF (150 mL) wasadded  N -hydroxybenzotriazole (HOBt, 5.64 g, 42 mmol), followed by dicyclohexylcarbodiimide (DCC; 8.60 g, 42 mmol). After stirring for l h,a solution of di- tert -butyl 4-amino-4-[2-( tert -butoxycarbonyl)ethyl]heptanedioate 5  (17.34 g, 41.7 mmol)in DMF (60 mL) was added and the solution stirred at 25 ℃  for 23 h.  The crystals were filtered and washed on thefilter with DMF (25 mL).  The solvent wasdistilled at 50 ℃ /1mm, and the residual oil was dissolved in ether (600mL).  Crystals were filtered, the ethereal solutionwas washed successively with 10% HCl (2 x100 mL), saturated NaHCO ₃ (2 x 100 mL), and brine (2 x 50 mL), then dried (Na ₂ SO ₄ ). The ether solution was filtered throughcelite and solvent was then removed  in vacuo  to afford 19.0 g of crude product, which waspurified on a silica column eluting with toluene/EtOAc (1:1) to furnish (60%)the white, non-crystalline ester  12 :14.0 g; mp 55-60 ℃ .   ¹ HNMR δ 1.43 (s, C H ₃ , 108H), 1.94-2.28 (m, C H ₂ C H ₂ ,64H), 5.87 (s, N H , 4H), 6.17 (s, C H =C H , 2H);  ¹³ C NMR (DMSO-d ₆ ) δ28.3 ( C H ₃ ), 29.3 ( C H ₂ C H ₂ ),56.8 ( C NH), 69.0 ( C SO ₂ ), 171.1 ( C O), 171.4 ( C O).

To a solution of amine  13  (106 mg, 0.3 mmol),Fmoc-Phe-OH (116 mg, 0.3 mmol), and HOBt (44.8 mg, 0.33 mmol) in anhydrous DMF(2 mL) was added DIC (56  µ L, 0.36 mmol).  The resulting mixture was stirred at roomtemperature overnight, and DMF was then evaporated under high vacuum.  The residue was dissolved in ethyl acetate (10mL), washed sequentially with saturated aqueous NaHCO ₃  and brine,and then dried over Na ₂ SO ₄ .  The evaporation of the solvent gave the crudeproduct that was directly submitted for the Fmoc removal without purification.  The crude product was dissolved in DMF (8 mL),piperidine (2.0 mL) was added, and the resulting solution was stirred at roomtemperature for 1 h.  Following thesolvent evaporation, the residue was purified by silica gel chromatography (50%ethyl acetate in hexanes to 10% methanol in chloroform) to provide product  14 (128 mg) in 85% yield as a mixture of two diastereomers. 1H NMR (CDCl3, 400MHz)  ‰  8.12-8.00 (2H, m), 7.90-7.80 (2H, m), 7.70-7.54 (2H, m), 7.42(2H, m), 7.35-7.20 (2H, m), 6.97-6.83 (3H, m), 5.32 (1H, m), 4.32 (1H, m),4.20-4.03 (2H, m), 3.96-3.80 (2H, m), 3.60 (1H, m), 2.98 (3H, m), 2.88 (2H, s),2.60 (1H, s), 2.00 (1H, m), 1.85 (2H, m), 1.77-1.55 (3H, m); MS (ES+)  m / z ) 501.4 (M + 1).

To a solution of amine 16  (0.284 mg, 1.19 mmol) and 5-hexenoic acid  15 (0.136 g,1.19 mmol) in CH ₂ Cl ₂  (12.0 ml) at 0 ℃ were added HOBt (0.177 g,1.31 mmol) and EDC (0.251 g,1.31 mmol).  The reaction mixture was stirredat room temperature for 10 h, then washed with 5% aqueous HCl (3 × 15.0 ml), 5% aqueous NaHCO ₃  (20 .0 ml),H ₂ O (20.0 ml), and brine (20.0 ml), and dried (Na ₂ SO ₄ ).  Purification by flash chromatography(CH3Cl/MeOH, 10%, Rf = 0.43) afforded amidoalkene  17  in 99%yield as a brown oil. 

A DMF solution (10 mL) containing HOBt (103 mg, 0.76mmol), EDC (192 mg, 1.0 mmol), and Boc-D-Ile (172 mg, 0.76 mmol) was stirred atroom temperature for 20 h.  A solution ofthe amino ketal  18  (0.41 g,0.76 mmol) and 4-methylmorpholine (0.17 mL, 1.5 mmol) dissolved in 10 mL of DMFwas then added to the reaction mixture.  After4 h the reaction mixture was partitioned between EtOAc and H ₂ O.  The organic layer was washed with H ₂ O,dried over MgSO ₄ , and concentrated under reduced pressure.  Flash chromatography (4:1 EtOAc/hexanes)afforded the Boc ketal  19  (0.44 g,0.59 mmol, 78%).

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