1. D. A. Ontjes, C. B. Anfinsen., J. Biol. Chem., 1969, 244, 6314
2. R. J. Bergeron, J. J. McManis., J. Org. Chem., 1988, 53, 3108; H. Newman., J. Org. Chem., 1965, 30, 1287; J. Quik, C. Meltz., J. Org. Chem., 1979, 44, 573; M. A. Schwartz, B. F. Rose et al., J. Am. Chem. Soc., 1973, 95, 612; D. L. Boger, D. Yohannes., J. Org. Chem., 1989, 54, 2498
3. M. Imazawa, F. Eckstein., J. Org. Chem., 1979, 44, 2039 4. S. B. King, B. Ganem., J. Am. Chem. Soc., 1994, 116, 562
5. D. Albanese, F. Corcella, D. Landini et al., J. Chem. Soc. Perkin Trans. I, 1997, 247
3.3.2.1 KOHÍÑÈ¥Èý·úÒÒõ£»ùʾÀý
OHNHCOCF3KOHMeOH, H2OO1O2OHNH2
Chambers, James J; Parrish, Jason C et al., J. Med. Chem., 2003, 46(16), 3526-3535
A solution of compound 1 (1.7 g, 5.4 mmol) in MeOH (250 mL) was cooled to 0¡ãC, and then 5 N KOH solution (30 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred overnight, and then the MeOH was removed by rotary evaporation. The residue was diluted with H2O (25 mL) and extracted with Et2O (4 x 100 mL), dried (Na2SO4), filtered, and evaporated to afford clear oil. This oil was dissolved in Et2O (100 mL), filtered through a plug of glass wool, and neutralized by the slow addition of oxalic acid (54 mL, 0.1 M in MeOH). The solvents were removed, and the resulting white residue was recrystallized from MeOH to afford compound 2 (0.9 g, 59%) as the hemioxalate salt, m.p 243 ¡ãC.
3.3.2.2 K2CO3ÍÑÈ¥Èý·úÒÒõ£»ùʾÀý
HN1NHCOCF35% K2CO3MeOH, H2OHN2NH2
Page 56 of 77
Whitlock, Gavin A; Carreira, Erick M et al., Helv. Chim. Acta., 2000, 83(8), 2007-2022 Compound 1 (45 mg, 0.18 mmol) was dissolved in 5% K2CO3 in MeOH/H2O (15 mL), and the soln. was stirred at 23¡ãC for 4 h. H2O (3 mL) was added, the soln. was saturated with NaCl, and then extracted with CH2Cl2 (5¡Á15 mL). The combined org. extracts were dried (Na2SO4) and concentrated under reduced pressure to afford compound 2 (23.5 mg, 85%).
4£®Íé»ùÀà
4.1 Èý±½¼×»ù£¨Trt£©
Èý±½¼×»ù£¨Trt£©ÊÇ50Äê´ú¿ªÊ¼ÓÃÓÚ¶àëĺϳɵģ¬ÏÖÔÚÌå»ý´óµÄTrt±»ÓÃÓÚ±£»¤¸÷ÖÖ°±»ù£¬Èç°±»ùËá¡¢ÇàÃ¹ËØ¡¢Í·æßÃ¹ËØµÈ¡£N-Trt-¦Á-°±»ùËáµÄõ¥²»ÄÜ·¢ÉúË®½â£¬ÐèÒª½ÏÇ¿µÄÈ¥±£»¤Ìõ¼þ£¬¦Á-ÖÊ×ÓͬÑù²»Ò×±»ÍÑÈ¥£¬ÕâÒâζ×Å£¬ÔÚ·Ö×ÓÖÐÆäËûµØ·½µÄõ¥¿ÉÒÔÑ¡ÔñÐÔµÄË®½â¡£
TrtµÄÁ¢Ìåλ×èµÄÓ°Ï컹±íÏÖÔÚ½ÓëÄ·´Ó¦ÖУ¬Trt-°±»ùËᣨ³ýTrt-GlyºÍTrt-AlaÒÔÍ⣩һ°ã²»ÄܲÉÓûìºÏËáôû·¨½ÓëÄ[1]£¬Trt-°±»ùËáµÄõ¥²»ÄÜË®½â£¬Ò²¾Í²»ÄÜÓõþµª·¨½ÓëÄ£¬¶øÖ»ÄܲÉÓÃDCCÕâÀà·½·¨À´½ÓëÄ¡£µ«TrtµÄÁ¢Ìåλ×èÖ»±íÏÖÔÚ¶ÔTrt-°±»ùËáµÄ·´Ó¦Ó°ÏìÉÏ£¬Trt-ëÄÔò²»´æÔÚÕâ¸öÎÊÌ⣬Òò´Ë¶Ô³¤Á´ëĵÄÄ©¶Ë°±»ùµÄ±£»¤À´Ëµ£¬Trt»¹ÊÇ¿ÉÓõģ¬ÌرðÊǶÔÓÚ´øÓк¬Áò°±»ùËáµÄëÄÀ´Ëµ£¬ÓÉÓÚ²»ÄܲÉÓô߻¯Çâ½âÀ´ÊµÏÖCbzºÍBocÖ®¼äµÄÑ¡ÔñÐÔÍÑÈ¥£¬²ÉÓÃTrtÔò½«ÓÐÆäÓÐÀûÖ®´¦¡£
1. L. Zervas, D. M. Theodoropoulos., J. Am. Chem. Soc., 1956, 78, 1359
4.1.1 Èý±½¼×»ùµÄÒýÈë
ÓÉÓÚTrtÓкܴóµÄÁ¢Ìåλ×裬³ý°±»ùËá²àÁ´ºÜСµÄTrt-¸Ê°±Ëáõ¥ÒÔÍ⣬һ°ãµÄTrt-°±»ùËáõ¥¶¼ÄÑÒÔÔí»¯£¬¶øÓúÜÇ¿ÁÒµÄÌõ¼þ£¨Èç¸ßΣ©ÔòÓÐÒýÆðÏûÐýµÄΣÏÕ¡£Òò´ËTrtµÄÒýÈëÒ»°ãÊDzÉÓÃÒÔÏ·´Ó¦À´ÊµÏֵġ£
Page 57 of 77
RCl+HOOCNH2Et3NNHRCOOHRCl+BnOOCNH21. Et3NNH2. H2/Pd-CRCOOH
¾¡¹Ü¿É²ÉÓÃÏÈÖÆµÃTrt-°±»ùËáÜÐõ¥£¬È»ºó¿ØÖÆÎüÊÕ1.1µ±Á¿µÄÇâÑ¡ÔñÐÔÇâ½âµÄ·½·¨£¬µ«ÓÉÓÚ×ÜÓв¿·ÖTrt±»Ç⻯£¬Òò´ËÐèÒª³ýÈ¥ËùÉú³ÉµÄ×ÔÓɰ±»ùËḱ²úÎï¡£ÓñÖõÈÈËÔø¾Ìá³ö[1]£¬½«°±»ùËáÐü¸¡ÓëCHCl3ÖУ¬¼ÓÈë2.2µ±Á¿µÄTrt-ClºÍ2.2µ±Á¿µÄEt3N£¬½Á°è·´Ó¦5-10СʱÏÈÉú³ÉTrt-°±»ùËáÈý±½¼×õ¥£¬È»ºóÓÃHCl/HOAc´¦Àí5-20·ÖÖÓÍÑÈ¥Èý±½¼×õ¥¶øµÃµ½Trt-°±»ùËá¡£ÁíÒ»¸ö°ì·¨ÊÇÓÃëĵÄõ¥Í¬Trt-Cl·´Ó¦µÃµ½Trt-ëÄõ¥£¬ºóÕßÈÝÒ×Ôí»¯¶ø²»´æÔÚTrtµÄÁ¢Ìåλ×è×÷Óá£ßÁ¿©¡¢ßÁßòºÍßäßòµÈÒ²¿ÉÓÃÀàËÆ·´Ó¦ÈÝÒ׵صõ½Á¼ºÃ²úÂʵÄTrt-ÑÜÉúÎï¡£ÁíÍ⣬ÀûÓÃTrt-Cl/Me3SiCl/Et3N[2]ºÍTrt-Cl/TMSCl/Et3N[3]Ò²ÈÝÒ׵õ½Trt-°±»ùËá¡£
1. ÓñÖý¡Ì«ÀÉ£¬¹¤ÌÙÊ¿ÀÉ., ÓлúºÏ³ÉлáÖ¾., 1971, 29, 599
2. Hoffman, Robert V; Maslouh, Najib et al., J. Org. Chem., 2002, 67(4), 1045-1056; Sim, Tae Bo; Rapoport, Henry et al., J. Org. Chem., 1999, 64(7), 2532-2536 3. Hoffman, Robert V; Tao Junhua, J. Org. Chem., 1998, 63(12), 3979-3985
4.1.1.1 °±»ùËáµÄÈý±½¼×»ùµÄÒýÈëʾÀý
OONH21OOHTrt-ClMe3SiCl, Et3NONHTrt2OOOH
Hoffman, Robert V; Maslouh, Najib et al., J. Org. Chem., 2002, 67(4), 1045-1056 Chlorotrimethylsilane (1.27 mL, 10.0 mmol) was added at room temperature to a stirred suspension of an compound 1 (1.61 g, 10.0 mmol) in 18 mL of CHCl3/MeCN (5:1). The reaction mixture was refluxed for 2 h and then cooled to 0 ¡ãC. Dropwise addition of triethylamine (2.79 mL, 20.0 mmol) was followed by a solution of trityl chloride (2.79 g, 10.0 mmol) in chloroform (10 mL). The resulting mixture was stirred for 1 h, and then methanol (2 mL) was added. After concentration, the pale yellow residue was partitioned between diethyl
Page 58 of 77
ether and water. The aqueous layer was extracted twice with diethyl ether (20 mL). The combined organic layers were dried (MgSO4) and concentrated to give compound 2 (2.14 g, 53%), which was used for the next step without further purification.
4.1.1.2 °±»ù´¼µÄÈý±½¼×»ùµÄÒýÈëʾÀý
OOH2NOHEt3N, CH2Cl21Ph3C-ClPh3CHN2OOOH
Gros, Christel; Boulegue, Cyril et al., Tetrahedron, 2002, 58(13), 2673-2680
Amino alcohol 1 (2.15 g, 12.3 mmol) and Et3N were dissolved in dry CH2Cl2 (60 mL). To the ice-bath cooled preceding solution, trityl chloride (3.43 g, 12.3 mmol) dissolved in CH2Cl2 (20 mL) was added dropwise over 15 min. After stirring 1 h at rt, the solvent was evaporated. The residue dissolved in AcOEt (100 mL) and followed by a flash column chromatography purification (AcOEt/cyclohexane 80:20) to afford alcohol 2 as an oil in: 83% yield.
4.1.2 Èý±½¼×»ùµÄÍÑÈ¥
TrtÈÝÒ×ÓÃËáÍÑÈ¥£¬ÈçÓÃHOAc»ò50%£¨»ò75%£©HOAcµÄË®ÈÜÒºÔÚ30¡æ»ò»ØÁ÷Êý·ÖÖÓ˳Àû³ýÈ¥¡£ÕâʱN-BocºÍO-But¿ÉÒÔÎȶ¨²»¶¯[1]¡£ÆäËûÈçHCl/MeOH[2]¡¢HCl/CHCl3¡¢HBr/HOAcºÍTFA[3]¶¼Äܷܺ½±ãµÄÍÑÈ¥Trt£¬ÓÃHCl/MeOH´¦ÀíTrt-Lys(Trt)OCH3¿ÉÒԵõ½Lys(Trt)OCH3£¬ËµÃ÷²àÁ´ÉϵÄTrt±È¦Á-Trt ¶ÔËá¸üÎȶ¨Ò»Ð©[4]¡£Cys(Trt)¡¢His(Trt)ºÍTry(Trt)µÈµÄ²àÁ´ÉϵÄN-Trt±ÈN¦Á-Trt ¶ÔËáÎȶ¨£¬Òò´Ë¿ÉÒÔ²ÉÓÃÊʵ±µÄËá½âÌõ¼þÑ¡ÔñÐÔÍÑÈ¥N¦Á-Trt¶ø±£Áô²àÁ´ÉϵÄN-Trt¡£
Trt¶ÔËáµÄÃô¸Ð³Ì¶È»¹ËæËùÓõÄËáµÄ²»Í¬¶øÒ죬ÀýÈçTrt¶Ô´×Ëá±È½ÏÃô¸Ð£¬ÔÚ80%µÄ´×ËáÖУ¬TrtµÄÍѳýËÙ¶È´óÔ¼±ÈBpoc¿ì7±¶£¬±ÈBoc¿ì21£¬000±¶£¬Òò¶ø¿ÉÒÔÔÚBoc»òMoz´æÔÚÏÂÑ¡ÔñÐÔµØÍÑÈ¥Trt¡£µ«ÈçÓÃ0.1M HBr/HOAcΪÊÔ¼Á£¬TrtÍÑÈ¥ËÙ¶È·´¶øÂýÓÚBocºÍMoz[1]¡£
TrtÒ²Äܱ»´ß»¯Çâ½âÍÑÈ¥[5]£¬µ«ÍÑÈ¥ËٶȱÈO-ÜлùºÍN-CbzÒªÂýµÃ¶à¡£¸ù¾ÝËùÓÃÊÔ¼ÁºÍÍÑÈ¥·½·¨µÃ²»Í¬£¬Trt±»·Ö½âËùÐγɵIJúÎïÒ²²»Í¬£¨¼ûÏÂʽ£©¡£
Page 59 of 77