Solid-Phase Synthesis of ɤ-Lactone and 1,2-Oxazine Derivatives and Their Efficient Chiral Analysis

Abstract

Derivatives of 3-methyl-3,6-dihydro-2H-1,2-oxazine-6-carboxylic acid prepared by regioselective hetero Diels-Alder reaction of arylnitroso compounds with sorbic acid were used for solid-phase synthesis of a library of derivatives that included modification of carboxylic group, dihydroxylation of double bond and cleavage of N-O bond. Derivatives of 2,3,4-trihydroxyhexanoic acid obtained from 3,6-dihydro-2H-1,2-oxazines after double bond dihydroxylation and N-O cleavage were used for simple and stereoselective formation of chiral lactones derived from 3,4-dihydroxydihydrofuran-2(3H)-one. The final compounds obtained as a mixture of stereoisomers were analyzed with use of chiral HPLC and SFC. HPLC analyses were not successful for all derivatives or required lengthy chromatography. On the other hand SFC afforded much shorter analyses and was effective for all studied derivatives. The method of synthesis and analysis is thus suitable for future study of stereoselective synthesis of lactones and other derivatives from single oxazine derivatives and application of high-throughput synthesis on solid-support and combinatorial chemistry.

Polymer-Supported Syntheses of Heterocycles Bearing Oxazine and Thiazine Scaffolds

“…Later, the stereochemical outcome of the solid-phase HDA reactions leading to 3,6-dihydro-2 H -1,2-oxazines was studied in detail by Hlavac et al using chiral supercritical fluid chromatography (SFC). , …”

“…18 Later, the stereochemical outcome of the solid-phase HDA reactions leading to 3,6-dihydro-2H-1,2-oxazines was studied in detail by Hlavac et al using chiral supercritical fluid chromatography (SFC). 19,20 The only report on the solid-phase synthesis of compounds bearing the 1,2-thiazine scaffold was by Lee. 21 First, thiazole intermediate 10 was synthesized from chloromethyl resin 8 in two steps.…”

Study of Enantioselective Catalysis of Nitroso-Diels-Alder Reaction on Solid Support

“…One of the reactions of general interest is nitroso‐Diels‐Alder (NDA) reaction. This reaction is used as a tool for synthesis of 3,6‐dihydro‐1,2‐oxazine derivatives, which are important intermediates in the synthesis of natural products and biologically relevant structures . In this reaction, nitroso dienophile 1 attacks diene 2 affording a mixture of stereoisomers and possibly regioisomers 3 a‐3 d (Scheme ) .…”