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2.3.2.1 ÈýÒÒ°·ÓÃÓÚÍѳýó˼×ÑõôÊ»ùʾÀý

STrFmocHNO1OAllylDEACH3CNH2NO2STrOAllyl

Shu-Li You and Jeffery W. Kelly., J. Org. Chem. 2003, 68, 9506

Diethylamine (30 mL) was added to a solution of 5 (5.63 g, 9 mmol) in CH3CN (30 mL), and the resulting mixture was stirred at 25 ¡ãC for 30 min to ensure complete removal of the Fmoc protecting group. After concentration in vacuo, the reaction mixture was azeotroped to dryness with CH3CN (2 x 30 mL) to give compound 2 (3.4 g, 89%).

20%µÄßßà¤ÓÃÓÚÍѳýó˼×ÑõôÊ»ùʾÀý1

NNNONHFmocPiperidineNHNONH2MeOHNH12

US6329389

Piperidine (0.66 ml) was addede to a solution of compound 1 (0.797 g) in MeOH (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 h, then concentrated and the residue was purified by alumina column chromatography (rthyl acetate/methanol = 10/1) to obtain compound 2 (0.382 g, 76%).

HNClOHNOHNOOHNHFmocHNOClHNOHNOOHNH2PiperidineDMF12

US6331640

Piperidine (0.88 ml, 0.89 mmol) was addede to a solution of compound 1 (116 mg, 0.18 mmol) in DMF (5 ml) at room temperature. The solution was stirred at room temperature for 30 min, and then solvent was evaporated. The resulting white solid was triturated with ether five times and dried in vacuo to give compound 2 (59 mg, 81%) as an off-white solid.

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2.4. Ï©±ûÑõôÊ»ù£¨Alloc£©

Ï©±ûÑõôÊ»ù£¨Alloc£©Í¬Ç°ÃæÌáµ½µÄCbz¡¢BocºÍFmoc²»Í¬£¬Ëü¶ÔËá¡¢¼îµÈ¶¼ºÜÎȶ¨£¬ÔÚËüµÄ´æÔÚÏ£¬Cbz¡¢BocºÍFmocµÈ¿ÉÑ¡ÔñÐÔÈ¥±£»¤£¬¶øËüµÄÍÑÈ¥Ôòͨ³£ÔÚPd(0)µÄ´æÔÚϽøÐС£

2.4.1 Ï©±ûÑõôÊ»ù£¨Alloc£©µÄÒýÈë

Alloc-ClÔÚÓлúÈܼÁ/Na2CO3¡¢NaHCO3ÈÜÒº»òßÁà¤ÖÐͬ°±»ù»¯ºÏÎï·´Ó¦Ôò¿ÉµÃµ½Aloc±£»¤µÄ°±»ùÑÜÉúÎï[1]¡£

1. E. J. Corey, J. W. Suggs., J. Org. Chem., 1973, 38, 3223

2.4.1.1°±»ùËáµÄÏ©±ûÑõôÊ»ù£¨Alloc£©µÄÒýÈëʾÀý

OHONH2OOOAlloc-Claq. NaHCO3, THFOOOHNHAlloc

Micale, Nicola; Vairagounder, Rajendran et al J. Med. Chem., 2004, 47(26), 6455-6458 To a stirred solution of compound 1 (3.0 g, 15.86 mmol) in a mixture of aq. NaHCO3 and THF (8/2, 20 mL) was added allylchloro formate (2.54 mL, 23.81 mmol), dropwise and at 0 ¡ãC. The mixture was stirred at room temperature for 12 h and then diluted with ethyl acetate and washed 3 N HCl, dried and the solvent removed in vacuo to give compound 2 as a pale yellow oil, which was used without further purification (3.55 g, 82%).

2.4.1.2Ò»°ã°±»ùµÄÏ©±ûÑõôÊ»ù£¨Alloc£©µÄÒýÈëʾÀý

1. HCl/EtOAcNBocCONH2HNBoc2. Alloc-Cl, Et3NNAllocCONH2HNAlloc12

H. Imamura; A. Shimizu et al., Tetrahedron, 2000, 56(39), 7705

To a solution of 17 (1.0 g, 1.97 mmol) in EtOAc (10 ml) was added 4 M HCl/EtOAc (20 mL), and the mixture was stirred for 6 h at room temperature. After evaporation, to the suspension of the residue in CH2Cl2 (40 mL) were added triethylamine (2.75 mL, 19.7 mmol) and allyl chloroformate (0.627 mL, 5.91 mmol) at -10¡ãC. The reaction mixture was poured into H2O

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and the whole was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/acetone = 8:1) to give 18 (863 mg, 92.1%) as a foam. [ a]D25=19.6 (c =1.0, CHCl3).

2.4.2 Ï©±ûÑõôÊ»ù£¨Alloc£©µÄÍÑÈ¥

Alloc±£»¤»ù¶ÔËá¡¢¼îµÈ½ÏÇ¿µÄÎȶ¨ÐÔ£¬ËüÃÇͨ³£Ö»ÓÃPd(0)£¬ÈçPd(PPh3)4»òPd(PPh3)2Cl2´æÔÚµÄÌõ¼þÈ¥±£»¤¡£ÀýÈ磬AllocÑÜÉúÎïÓÃPd(PPh3)4/Me2NTMS´¦Àí£¬¿ÉÒԵõ½Ò×Ë®½âµÄ°±»ù¼×ËáTMSõ¥ [1]¡£ÍÑÈ¥º¬ÁòÑÜÉúÎïÖеÄAlloc ʱ£¬Èçµ°°±ËᣬPd(PPh3)4/¶þ¼×»ù»·¼º¶þͪ/THÔò²»»á±»¶¾»¯[2]¡£Èç¹ûÔÚËáÐÔÌõ¼þÏÂÍѳýAlloc£¬Ôò×îºÃ²ÉÓÃPd(PPh3)2Cl2/Bu3SnH/p-NO2C6H4OH/CH2Cl2[3]¡£ÔÚÒìÎìÏ©õ¥»òÈâ¹ðËáõ¥´æÔÚÏ£¬¿ÉÓÃPd(OAc)2/TPPT/CH3CN/Et3N/H2OÈ¥±£»¤£¬µ«Ëæʱ¼äµÄÔö¼Ó£¬ÕâЩõ¥Ò²»á·´Ó¦£¬²¢ÇÒ°±»ù¼×ËáÒìÎìÏ©õ¥ºÍÏ©±û»ù̼Ëáõ¥Í¬Ñù±»¶ÏÁÑ[4]¡£µ±¼ÓÈëBoc2O¡¢AcCl¡¢TsCl¡¢»ò¶¡¶þËáôûʱ£¬Pd(PPh3)2Cl2/Bu3SnH¿É½«Alloc»ùת±äΪÆäËüµÄ°·ÑÜÉúÎï¡£ÁíÍ⣬AllocÒ²¿ÉÔÚPd(PPh3)4/HCOOH/TEA[5]»òAcOH/NMO´ß»¯ÍÑÈ¥[6]¡£

1. A. Merzouk, F. Guibe., Tetrahedron Lett., 1992, 33, 477

2. H. Kunz, C. Unverzagt., Angew. Chem. Int. Ed. Engl., 1984, 23, 436

3. O. Dangles, F. Guibe et al., J. Org. Chem., 1987, 52, 4984; P. Four, F. Guibe., Tetrahedron Lett., 1982, 23, 1825

4. S. Lemaire-Audoire, M. Savignac et al., Tetrahedron Lett., 1994, 35, 8783; E. Blart, J. M. Bernard et al., Tetrahedron Lett., 1997, 38, 2955; J. P. Genet, E. Blart et al., Tetrahedron Lett., 1993, 34, 4189

5. Y. Kanda, H. Arai et al., J. Med. Chem., 1992, 35, 2781 6. J. Lee, J. H. Griffin, T. I. Nicas., J. Org. Chem., 1996, 61, 3983

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2.4.2.1 Pd(PPh3)4-THFÌåϵÍѳýÏ©±ûÑõôÊ»ù£¨Alloc£©Ê¾Àý

EEOOOTMSNHAllocEEOPd(PPh3)4THFOOTMSNH2

Y. Matsushima; H. Itoh etal., J. Chem. Soc. Perkin Trans. 1., 2004, 7, 949

To a solution of the Alloc protected ester (140.7 mg, 0.2.23 mmol) and 1,3-dimethylbarbituric acid (228 mg, 1.46 mmol) in THF (15 mL) was added tetrakis(triphenylphosphine)palladium (43.9 mg, 0.0379 mmol, 17 mol%), and the resulting mixture was stirred at rt for 27 h. The mixture was then poured into saturated aq. NaHCO3 and extracted four times with Et2O. The combined extract was dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (CHCl3/MeOH, 20 : 1 to 2 : 1) to give the corresponding free amino ester as a colorless oil (79.5 mg, 65%).

2.4.2.2 Pd(PPh3)4/Me2NTMSÌåϵÍѳýÏ©±ûÑõôÊ»ù£¨Alloc£©Ê¾Àý

ONSiOSHNMeOOONSPd(PPh3)4, TMS-DMATMS-TFA, CH2Cl2MeOONHAllocONSiOSHNONSNH2

P. Angehrm; S. Buchmann et al., J. Med. Chem., 1992, 47(6), 1487

To a solution of 112 (0.97 g, 1.4 mmol) in CH2Cl2 (19 mL) were added dimethylamino- trimethylsilane (1.32 mL, 8.4 mol) and trimethylsilyl trifluoroacetate (1.45 mL, 8.4 mmol). The solution was stirred at 20 ¡ãC for 10 min, and then Pd(PPh3)4 (97 mg, 0.084 mmol) was added and stirring was continued for 2.5 h. The mixture was evaporated and the residual oil was dissolved in EtOAc (50 mL). The solution was washed with 10% aq NaHCO3 and brine, dried, and evaporated. The residue was chromatographed (SiO2; EtOAc/hexane 1:2) to give 113 (0.67 g, 78%): foam; TLC Rf ) 0.27 (EtOAc).

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