Synthesis of 1,4-Oxazepane-2,5-diones via Cyclization of Rotationally Restricted Amino Acid Precursors and Structural Reassignment of Serratin

Several natural products containing
a 1,4-oxazepane-2,5-dione-core
are known. One example is serratin, isolated from Serratia
marcescens. Because of the presence of a carboxylic
amide, which has a preference for a trans-conformation,
and the presence of a labile lactone in this core, many synthetic
methodologies commonly used for the cyclization toward medium-sized
heterocycles cannot be applied. As N-acyl amino acids lacking a third
substituent at nitrogen failed to undergo ring-closure, several N-protecting groups were evaluated. With the use of the removable
PMB-group, an N-unsubstituted 1,4-oxazepane-2,5-dione
was synthesized. Via the application of pseudoprolines (i.e. serine-derived
oxazolidines as another type of protecting group), a compound with
the presumed structure of the natural product serratin was obtained.
As a result of the differences in spectral data, the incorrect structural
assignment of the natural product serratin was identified. Instead
of the predicted seven-membered heterocycle, a symmetrical serratamolide
analogue is proposed to be the correct structure of serratin.