Herein, we report a simple synthesis of disubstituted pyrazino‐oxazines with controlled stereochemistry using readily available building blocks: N‐Fmoc‐protected α‐amino acids and 2‐bromo ketones. The convenient solid‐phase synthesis afforded polymer‐supported derivatives of N‐alkylated N‐acylated tert‐butylserine, which were subjected to spontaneous cyclative cleavage to yield the corresponding pyrazine intermediates. The target 1,7,8,9a‐tetrahydropyrazino[2,1‐c][1,4]oxazine‐6,9‐diones were obtained in two steps by acid‐mediated cleavage of the tert‐butyl group followed by cyclization of the oxazine scaffold.

Synthesis of triazolo[1,5‐a][1,4]diazepin‐6‐ones on solid support is reported in this article. Amino acids immobilized on Wang resin were nosylated and alkylated with propargyl alcohol, but‐2‐yn‐1‐ol or different 3‐phenylprop‐2‐yn‐1‐ols using Mitsunobu alkylation conditions. After denosylation, acylation with Fmoc‐azidoalanine yielded linear precursors that were thermally cyclized on resin to give immobilized triazolodiazepinones. After cleavage from the polymer support, the target compounds were obtained in high crude purities and good overall yields. Furthermore, the synthetic approach was applied to convenient solid‐phase synthesis of oligopeptide containing the triazolodiazepinone moiety as the peptidomimetic heterocyclic constraint.

In this review, we summarize synthetic approaches to preparing single or fused oxazine and thiazine derivatives using solid-phase synthesis (SPS). The literature survey revealed that diverse compounds bearing variously functionalized 1,2-oxazine, 1,3-oxazine, or 1,4-oxazine scaffolds and the corresponding thiazines are accessible by SPS. The latest contributions involving the stereoselective polymer-supported syntheses of morpholines indicate that the field is continuing to expand.

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Herein, we report the stereoselective synthesis of trisubstituted benzoxazino[4,3-b][1,2,5]thiadiazepinone 6,6-dioxides from polymer-supported Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH. After the solid-phase synthesis of N-alkylated-N-sulfonylated intermediates using various 2-nitrobenzenesulfonyl chlorides and bromoketones, the target compounds were obtained via trifluoroacetic acid (TFA)-mediated cleavage from the resin, followed by cyclization of the diazepinone scaffold. Except for the threonine-based intermediates, the inclusion of triethylsilane (TES) in the cleavage cocktail yielded a specific configuration of the newly formed C chiral center. The final cyclization resulted in minor or no inversion of the C stereocenter configuration.