12 May 2014 (online)
The de novo synthesis of peptides is one of the key interests of organic chemists. Dehydroamino acids are an important class of molecules and are widely recognized as excellent synthetic precursors for non-natural amino acids. They are also seen as structural units in many biologically active peptides. The 2-phthalimidoacrylates are dehydroamino acids derivatives. The amino and the carboxylic acid groups are protected as N-phthalimido and carboxylic ester groups. Although 2-phthalimidoacrylates are enamides, the olefin is substituted with electron-withdrawing groups. These features allow versatile modifications of the alkene under a myriad of reaction conditions.
The synthesis of 2-phthalimidoacrylates was first described by Brown and Smale in a three-step sequence starting from threonine methyl ester. Trost and co-worker shortened the synthesis to a single step using triphenylphosphine as a nucleophilic catalyst (Scheme ). Phthalimide adds to various propiolates selectively at the α-position in excellent yields. This reaction provides convenient access to the 2-phthalimidoacrylates and is amendable to scaling up.
2-Phthalimidoacrylates are very stable and can be kept on the benchtop for many years without any noticeable decomposition. They have an indefinite shelf life if they are kept at 4 °C. In addition, methyl 2-phthalimidoacrylate is commercially available.
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