Polymer-Assisted Synthesis of Single and Fused Diketomorpholines

The synthesis of different diketomorpholines via N-acyl-3,4-dihydro-2H-1,4-oxazine-3-carboxylic acids is reported in this article. The key intermediates were prepared using a convenient solid-phase synthesis starting from polymer-supported Ser­(tBu)-OH. After subsequent sulfonylation with 4-nitrobenzenesulfonyl chloride (4-Nos-Cl), alkylation with an α-bromoketone, cleavage of the 4-Nos group and acylation with an α-halocarboxylic acids, acid-mediated cleavage from the resin yielded dihydrooxazine-3-carboxylic acids in high crude purities. Depending on the reaction conditions, exposure to base resulted in cyclization to either oxazino­[3,4-c]­[1,4]­oxazine-diones or 3-methylidenemorpholine-2,5-diones. Further reaction with triethylsilane-trifluoroacetic acid (TES/TFA) led to olefin reduction, in the case of oxazino­[3,4-c]­[1,4]­oxazine-dione with full control of the newly formed stereocenter.