Ammonium salts, unwanted formation

Activation with sulfonic acid chlorides is more general, rendering amides with the possible participation of symmetric anhydrides after disproportionation. This method has also found use in the synthesis of modem 3-lactam antibiotics. However, in peptide chemistry this activation method leads to unwanted side reactions, like formation of nitriles in the cases of glutamine and asparagine, and racemization. In a convenient one-pot procedure, the carboxylic acids are activated by sulfonyl chlorides under solid-liquid phase transfer conditions using solid potassium carbonate as base and a lipophilic ammonium salt as catalyst. ... 

If the amine acts as an acylation catalyst, the potential exists for an unwanted side reaction to occur. It is well known that under anhydrous conditions acyl ammonium salts derived from the reaction of a chloroformate and a tertiary amine can decompose to form urethanes. We have recently reported a rate constant (1.3 0.2 min ) for the case involving triethylamine and phenyl chloroformate in methylene chloride at 39°C (see Scheme 4). Formation of urethanes in this manner under normal interfacial conditions to form high MW polymer would have minimal effects on the properties of the polymer and may not even be observed. However, urethane formation in the cyclization reaction would produce a capped oligomer which cannot cyclize, therefore leading only to polymer. In this manner, a fraction of the amine used in the reaction could produce a significant level of unwanted high MW polymer. Evidence for the formation of urethanes during the preparation of cyclics will be presented later in this paper. 

Introduction of the C2 sulfonamide is accomplished via sulfonylation with chlorosulfonic acid, conversion to the sulfonyl chloride using thionyl chloride, and amidation using concentrated ammonium hydroxide in tetrahydrofuran. Reduction of the 4-acetamido compound using borane-tetrahydrofuran complex provides the 4-ethylamino derivative. The 45,65-frans diastereomer is selectively crystallized as its maleate salt from acetone in the presence of the unwanted 4R,6S-cis diastereomer. Neutralization of the maleate salt and extraction of the free base in ethyl acetate, followed by formation of the hydrochloride salt, yields crude dorzolamide hydrochloride. 

In the past decade, several new approaches for controlled NCA polymerization based on the classical primary amine initiation have been reported. In 2003, Dimitrov and Schlaad reported the controlled ( ammonium mediated ) polymerization of ZLL-NCA at elevated temperature using primary amine hydrochloride salts as initiators (Figure 4.3). The initiator reactivity most likely is due to the formation of a small amount of free amine by reversible dissociation of HCl. This equilibrium is strongly shifted toward the dormant amine hydrochloride species. Consequently, as soon as a free amine reacts with an NCA, the resulting adduct is immediately protonated and prevented from further reaction. The presence of protons in the system suppresses formation of unwanted NCA anions ( activated monomers ). The obtained polypeptide blocks exhibit a very narrow, close to a Poisson, molar-mass distribution. 

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