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

PLoS One. 2016 Nov 28;11(11):e0166558. doi: 10.1371/journal.pone.0166558. eCollection 2016.

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.

MeSH terms

  • Chromatography, High Pressure Liquid
  • Cycloaddition Reaction
  • Lactones / chemical synthesis
  • Lactones / chemistry*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Oxazines / chemical synthesis
  • Oxazines / chemistry*
  • Solid-Phase Synthesis Techniques
  • Stereoisomerism

Substances

  • Lactones
  • Oxazines

Grants and funding

This work was supported by Ministry of Education, Youth and Sport of the Czech Republic; IGA_PrF_2016_020; http://www.msmt.cz/, the European Social Fund; CZ.1.07/2.3.00/20.0009; http://ec.europa.eu/esf/home.jsp, National Program of Sustainability; LO1304; http://www.msmt.cz/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.