H2/Pd-CPh3C-HHCl/CHCl3R1NHR2OHCl/MeOHHCl/H2OPh3C-ClPh3C-OHPh3C-OMeHOAcPh3C-OAc

1. 1. L. Zervas, D. M. Theodoropoulos., J. Am. Chem. Soc., 1956, 78, 1359; F. C. McKay, N. F.

Abertson., J. Am. Chem. Soc., 1957, 79, 4686; R. Schwyzer, W. Rittel., Helv. Chim. Acta., 1961, 44, 159

2. L. Hyun-Suk, P. Jeong-Ju et al., Bioorg. Med. Chem. Lett., 2004, 10, 2499; K. Yuji, T.

Ryuichi et al., Bioorg. Med. Chem., 2002, 10, 3829

3. S. Rita, K. Yeong-Sang et al., Tetrahedron Lett., 2003, 8, 1537

4. B. Bezas, L. Zervas., J. Am. Chem. Soc., 1961, 83, 719; G. Amiard, B. G. Offinet., Bull. Soc. Chim.

France., 1956, 698

5. Chandrasekhar, S., Babu, B. Nagendra et al., Tetrahedron Lett., 2003, 10, 2057; E. Janos,

K. Gyoergy et al., Tetrahedront., 2002, 44, 8921

TFA脱去三苯甲基示例

HFmocHNHTrtHNO1SOOHOTFACHCl3FmocHNHH2NO2SOOO

M. Firouz Mohd Mustapa, Richard Harris, Nives Bulic-Subanovic et al., J. Org. Chem., 2003, 21, 8185; S. Vinay, M. Mizio et al., Tetrahedron, 2002, 44, 9101

Compound 1 (3.5 g, 4.6 mmol) was treated with a 5% solution of trifluoroacetic acid (1.4 mL, 18 mmol, 4 equiv) in CHCl3 (27 mL) under inert conditions for 4 h. The resulting solution was diluted with CHCl3 (200 mL) and washed with sodium hydrogen carbonate (5% aq w/v, 2

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× 75 mL) and water (2 × 50 mL). The solvent was removed in vacuo. The material was then redissolved in CHCl3 (20 mL) and MeOH (20 mL), and the solvents were again removed in vacuo to yield compound 2 (2.1 g, 87%) as a pale yellow liquid.

4.1.2.2 TFA-TIS脱去三苯甲基示例

OTrtHNOO1ONHFmocTFATIS, CH2Cl2H2NOO2OOHNHFmoc

Swall, Vinay; Matteuccl et al., Tetrahedron, 2002, 58(44), 9101-9110

Compound 1 (2.0 g, 2.71 mmol) was stirred with TFA (4.9mL), CH2Cl2 (4.9mL) and TIS (0.2 mL) for 1 h. Solvent was removed in vacuo and the residue purified by column chromatography (SiO2, MeOH/CHCl3, 1:9 v:v) to afford compound 2 (1.16 g, 91%) as a white solid.

4.1.2.3 TFA-Et3SiH脱去三苯甲基示例

TBSOTrtHN1NBocOTFAOBnEt3SiH, CH2Cl2H2N2NHOBnTBSOO

Pickersgill, I. Fraser; Rapoport, Henry; J. Org. Chem., 2000, 65(13), 4048-4057

To a stirred solution of compound 1 (3.34 g, 3.82 mmol) and triethylsilane (0.64 mL, 4.01 mmol) in CH2Cl2 (16 mL) cooled to 0 °C was added dropwise TFA (16 mL). The resultant colorless solution was allowed to warm to rt, with stirring continued for 1 h. The solvents were evaporated, the residue was triturated with hexanes (5 x 50 mL), the hexane extracts were discarded, and the oily residue was partitioned between CHCl3/IPA (250 mL, 3/1) and 1 M NaOH (precooled to 0 °C, 100 mL). The aqueous phase was extracted with further portions of CHCl3/IPA (2 x 200 mL, 3/1), and the combined organic phase was dried, filtered, and evaporated to give compound 2 (2.04 g, 100% crude yield) as a pale yellow oil.

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4.1.2.4 HOAc脱去三苯甲基示例

NHTrtNH1HOAcH2ONH2NH2

Vago, Istvan; Kalaus, Groergy et al., Heterocycles, 2001, 55(5), 873-880

0.85 g (2 mmol) of compound 1 was dissolved in the mixture of 20 mL of acetic acid and 0.5 mL of water. The solution was heated under argon at 60 oC for 1 h, and then allowed to cool to rt. The resulted dark solution was diluted with 200 mL of water; the triphenylmethanol was removed by extraction with ether. The pH of the watery phase was adjusted to a value of 8 with sodium carbonate solution, extracted with dichloromethane; the extract was dried with magnesium sulfate, evaporated to dryness in vacuumto give, compound 2 (0.24 g ,64 %) as unstable brown oil.

4.1.2.5 TBS和Boc官能团存在下用BF3-HOAc脱去三苯甲基示例

OTBSTrtHN1NHBocBF3.Et2OAcOHH2N2OTBSNHBoc

Pickersgill, I, Fraser; Rapoport, Henry; J. Org. Chem., 2000, 65(14), 4048-4057 To a solution of 32 (2.67 g, 3.98 mmol) in CH2Cl2 (27 mL) cooled to 0 °C were added glacial acetic acid (6.7 mL) and BF3.Et2O (0.529 mL, 4.17 mmol) dropwise, and the mixture was stirred at 0 °C for 2 h. Cold (0 °C) 1 M NaOH (160 mL) was added and the mixture partioned between CHCl3/IPA (320 mL, 3/1) and cold (0 °C) 1 M NaOH (66 mL), followed by extraction with further portions of CHCl3/IPA (2 x 160 mL, 3/1). The combined organic phase was dried, filtered, and evaporated to a residue which was chromatographed (CH2Cl2/MeOH, 19/1 to 9/1) to give 33 (1.50 g, 88%) as a colorless oil: [α]22D = +3.1 (c = 1.0, CHCl3).

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4.2 2,4-二甲氧基苄基（DMB）

2,4-二甲氧基苄基（DMB）是较稳定的氨基保护基之一, 对催化氢解较Cbz、PMB和Bn稳定，故用H2/8%Pd-C/EtOH处理，则可除去Bn，而保留N-DMB[1]。同样，用Pd(PPh3)4/HOAc/THF处理，则可保留N-DMB, 而除去Alloc[2]。酰胺的苄基，常规加氢方法不易脱除，但DMB和PMB容易脱除。在设计合成路线时，2,4-二甲氧基苄胺常被用为氨的等价物加以使用。

1．Simig, Gyula; Doleschall, Gabor et al., Tetrahedron, 1985, 41(2), 479-484

2．Boeckman, Robert K; Weidner, Charles H et al., J. Am. Chem. Soc., 1989, 111(20), 8036-8037

4.2.1 2,4-二甲氧基苄基（DMB）引入

2,4-二甲氧基苄基（DMB）一般由ArCHO/NaBH3CN或NaBH(OAc)3[1]还原胺化类引入。

1. Moore, M. Caragh; Cox, Russell J et al., Tetrahedron, 1998, 54(31), 9195-9206

4.2.1.1 2,4-二甲氧基苄基（DMB）引入示例

MeOOMeCOOMeNHOMeCOOMeNH2OHCNaBH3CN/MeOH1OMe

Moore, M. Caragh; Cox, Russell J et al., Tetrahedron, 1998, 54(31), 9195-9206 Methanolic HCl was added to a stirred solution of L-phenylalanine methyl ester (4.33 g，24.16 mmol) in methanol (100 mL) to adjust to pH 6. 2,4-Dimethoxybenzaldehyde (4.82, 29.00 mmol) was then added, the solution stirred at 20°C for 30 min and then NaBH3CN (2.20 g，35.01mmol) was added and the reaction stirred for a further 16h. The solvent was removed in vucuo, water (50 mL) added and the solution extracted with diethyl ether (3x 100 mL). The organic extracts were combined: washed with an aqueous solution of FeSO4, dried (MgSO4), filtered and reduced in vucuo, to afford a crude pruduct as a pale yellow oil. Impurities of 2,4-dimethoxybenzylalcohol were removed by distillation under reduced presure

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