Coupling Reagents Universit233; ParisSud（耦合试剂Universit233;）.pdf

Coupling Reagents 1. COUPLING REAGENTS : Structure and acronyms 2 2. CARBODIIMIDE 3 1.a. N,N’-Dicyclohexylcarbodimide (DCC) 3 DCC/HOBt coupling experimental procedure: 4 1.b. N-(3-Dimethylaminopropyl)-N’-ethylcarbonate (EDC) 5 EDC coupling experimental procedure: 5 3. Phospohnium uroniums 5 2.a (benzotriazol-1-yl-oxy-tris(dimethylamino) phosphonium hexafluorophosphate) BOP , and PyBOP 5 2.b. (O-benzotriazol-1-yl-N,N,N ,N -tetramethyluronium hexafluorophosphate ) HBTU 6 HBTU coupling experimental procedure: 7 4. Secondary amine coupling 8 5. Acid halogenations 8 6. Recent coupling reagents 9 6.a (Ethyl cyano(hydroxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate. (PyOxim) 9 6.b. 1-[(1-(Cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino)] uranium hexafluorophosphate (COMU) 10 1. COUPLING REAGENTS : Structure and acronyms 2. CARBODIIMIDE DCC and EDC are often used with an additive: This is probably the most common method of coupling segments, with HOBt as the most efficient additives. The additive is essential to reduce isomerization to acceptable levels. 1.a. N,N’-Dicyclohexylcarbodimide (DCC) 1 Introduced in peptide synthesis by Sheehan and Hess in 1955. Mechanism Symmetrical anhydrides are stable enough to be isolated but not stable enough to be stored for future use. Problem when DCC is used alone (transposition O to N acylurea is observed Path A) 1 JC Sheehan, GP Hess. A new method of forming peptide bonds. (carbodiimide) J. Am. Chem. Soc. 1955, 77, 1067. Side product observed when DCC is used alone (transposition O to N acylurea Path A) 1-Hydroxybenzotriazole (HOBt) as an additive that suppresses N-acylurea formationby protonation of the O-acylisourea (Path B