ABSTRACT
Tertiary amines are employed for abstracting protons from N-alkoxycarbonylamino acids to initiate onium salt-mediated reactions (see Sections 2.16-2.19) and for neutralizing protons that are generated during aminolysis of the acid halides (see Sections 7.11 and 7.12). At the same time, the amines may abstract protons that were not intended, such as the α-proton of the residue (see Section 4.2) or the NH proton of the urethane that leads to 2-alkoxy-5(4H)-oxazolone formation (see Section 1.10). Under ordinary conditions, the secondary reactions do not occur or are of no consequence. However, there are situations in which unwanted deprotonations do occur, and they may be followed by enolization, which means isomerization of the residues. Situations in which the presence of a base can lead to isomerization include reactions of highly activated compounds that are not consumed quickly, tertiaryamine initiated coupling reactions carried out in the presence of excess base, and repeated exposure to secondary amines of peptides that have an esterified cysteine residue at the carboxy terminus. Examples of enantiomerization sustained by compounds left in the presence of basic amines appear in Figure 8.1. The acid halides that generate oxazolone in the presence of a base (see Section 4.17) isomerize very quickly; no isomerization occurs when they are aminolyzed under normal operating conditions. Even Fmoc-Pro-Cl is not immune to the effect of a base (Figure 8.1), having been isomerized during an attempt to react it with the hydroxymethyl group of a linker-resin. Reducing the temperature and amount of pyridine allowed esterification without isomerization.
