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General procedure: Synthesis of Resins 135a-k: Immobilisation of Fmoc-AA1 -OH 2-Chlorotrityl chloride resin (matrix: copoly(styrene-l% DyE), 100-200 mesh, loading: 1.3 mmol/g; 10 g, 13 mmol) was suspended in dry CH2C12 (100 mE), shaken for 50 mm and filtered. The resin was suspended in dry CH2C12 (80 mE). A soln of Fmoc-AA1-OH (10.3 mmol) and i-Pr2NEt (4.4 mE, 26 mmol) in DMF (20 mE) was added. The mixture was shaken at it for 2.7 h with N2 bubbling through. The resin was filtered and washed (CH2C12, DMF, CH2C12). Capping:The resinwas shaken in CH2C12/MeOH/i-Pr2NEt 15:2:3 (100 mE) for 0.5 h and filtered. The capping step was repeated twice. The resin was filtered, washed (CH2C12, DMF, CH2C12, MeOH) and dried i.v. to afford resin 135. 2. Synthesis of Ex. 195a,b,e-h,j; Ex. 196c,i,k and Ex. 197d Fmoc Cleavage: The resin 135 (90-107 mg, ca 70 tmol) was swollen in DMF (1 mE) for 1 h and filtered. Then it was suspended in a soln of 2% v/v DI3U in DMF (1 mE), shaken for 10 mm filtered and washed (DMF). The deprotection step was repeated once. The resin 136 was filtered and washed (DMF).Coupling of Fmoc-AA2-OH: The resin 136 was suspended in DMF (1 mE). i-Pr2NEt (280 tmol), Fmoc-AA2- OH (140 tmol) and HATU (140 tmol) were added. The mixture was shaken for 40 mm, filtered and washed (DMF). The coupling step was repeated once. The resin 137 was filtered and washed (DMF).Fmoc Cleavage: The resin 137 was treated with 2% v/v DI3U in DMF (1 mE) as described above to afford resin138.Coupling of Fmoc-AA3-OH: The resin 138 was suspended in DMF (1 mE). i-Pr2NEt (280 tmol), Fmoc-AA3- OH (140 tmol) and HATU (140 tmol) were added. The mixture was shaken for 40 mm, filtered and washed (DMF). The coupling step was repeated once. The resin 139 was filtered and washed (DMF).Fmoc Cleavage: The resin 139 was treated with 2% v/v DI3U in DMF (1 mE) as described above to afford resin140.Coupling of Alloc-protected amino acid 84: The resin 140 was suspended in DMF (1 mE). i-Pr2NEt (560 tmol), 84 (36 mg, 84 tmol) and PyI3OP (140 tmol) were added. The mixture was shaken for 1 hand filtered. The resin 141 was washed (DMF). The coupling step was repeated once. The resin was filtered and washed (DMF, CH2C12).Alloc Cleavage: The resin 141 was suspended in CH2C12 (1 mE). Phenylsilane (0.18 mE; 1.4 mmol) and Pd(PPh3)4 (8 mg, 7 tmol) were added. The mixture was shaken for 15 mm and filtered. The deprotection step was repeated once. The resin 142 was filtered and washed(CH2C12, DMF, MeOH, CH2C12). Release of the cyclization precursor: The resin 142 was treated with HFIP/CH2C12 2:3 (1 mE) for 30 mm, filtered and washed (CH2C12). The cleavage step was repeated once. The combined filtrates and washings were concentrated, taken up in CH3CN (3 mE), concentrated and dried i.v. to afford crude 143a-k. Ring closure and cleavage of side chain protective groups: Crude 143 was dissolved in a soln of i-Pr2NEt (98 pL; 570 pmol) in dry DMF (4 mE). This soln was then added dropwise to a soln of FDPP (41 mg, 106 tmol) in DMF (20 mE). The soln was stirred at rt for 5 h and the volatiles were evaporated. The residue was treated with sat. aq. Na2CO3 soln (4 mE) and extracted with CHC13 (9 mE). The organic layer was filtered through a pad of Mg504. The filtrate was con-centrated to afford crude Ex. 195a-k. Crude products Ex. 1 95a,b,e-h,j were purified by prep. HPEC to afford Ex. 1 95a, b,e-h,j. |
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