Acyl fluorides reaction with aminals

For reactions carried out in homogeneous solution or under solid-phase conditions the use of Fmoc amino acid chlorides is limited by the competition between their aminolysis and the formation of the less reactive oxazol-5(4//)-ones in the presence of tertiary amines, which are essential components of such reaction systems. To improve the results under these conditions a hindered base, e.g. 2,6-di-/er/-butylpyridine, can be used as a hydrogen chloride acceptor since conversion to oxazol-5(4//)-one is slow with such bases. Although shown to be advantageous in certain cases, Fmoc amino acid chlorides are used in homogeneous solution synthesis only in particular cases. They react efficiently in the presence of pyridine with weak nucleophiles such as imine 2P l (Scheme 2) where other activated species such as an active ester, anhydride, acyl fluoride, and acyl imidazolide fail. 

A typical preparation protocol is shown in Scheme 2.146. In the first step in a one-pot reaction, 2,2 -[(l ,l )-hydrazine-l,2-diylidenebis(methanylylidene)] dibenzoic acid is reacted with 1,2-diphosphinobenzene and succinyl chloride to create the racemic bisdiazaphospholane with moderate yield. After condensation of all four carboxylic groups with an optically pure amine, diastereomeric amides are formed, which can be finally separated by liquid chromatography. By using phthaloyl chloride in the cyclization step or other enantiopure aryl amines, several analogs are accessible. For the linkage of sterically encumbering or less nucleophilic amines, the route via the corresponding acyl fluorides proved to be more successful [65]. 

The silicon linker 1.17 (74), prepared by Grignard reaction of a 4-bromoarylsilane with commercial formyl PS resin, was used to support acids, alcohols, and amines either as such via its acyl imidazole derivative cleavage with TBAF (tert-butylam-monium fluoride) in DMF for 3 h at 60 °C, or with CsF in DMF for 18-24 h at 90 °C validated the release of the three different functionalities. 

While there is evidence from IR investigations for the formation of traces of oxazol-5(4//)-one by treatment of Fmoc-protected amino acid fluorides, e.g. Fmoc-Val-F, with DIPEA, this reaction is not rapid enough to compete with the acylation process. In contrast to Fmoc amino acid chlorides, the related fluorides can be used in homogeneous systems with tertiary amines as efficient agents in peptide synthesis. 

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