A chiral phosphazane reagent strategy for the determination of enantiomeric excess of amines

• Published in: Chemical science (Cambridge) Vol. 13; no. 18; pp. 5398 - 5412
• Main Authors: Peel, Andrew J, Terzopoulos, Alexandros, Jethwa, Rajesh B, Choudhury, Dipanjana, Niu, Hao-Che, Bond, Andrew D, Slaughter, Jonathan, Wright, Dominic S
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 11.05.2022; Royal Society of Chemistry; The Royal Society of Chemistry
• Subjects: Amines; Chemical equilibrium; Chemistry; Chemistry, Multidisciplinary; Enantiomers; Locking; Measurement methods; NMR spectroscopy; Organic chemistry; Physical Sciences; Reagents; Rings (mathematics); Science & Technology; IDENTITY; ANTIPROLIFERATIVE ACTIVITY; ABSOLUTE-CONFIGURATION; CYCLODIPHOSPHAZANE; PURITY; LIGANDS SYNTHESIS; ASSIGNMENT; I COMPLEXES; METAL-COMPLEXES
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d2sc01692c

Methods for measuring enantiomeric excess ( ee ) of organic molecules by NMR spectroscopy provide rapid analysis using a standard technique that is readily available. Commonly this is accomplished by chiral derivatisation of the detector molecule (producing a chiral derivatisation agent, CDA), which is reacted with the mixture of enantiomers under investigation. However, these CDAs have almost exclusively been based on carbon frameworks, which are generally costly and/or difficult to prepare. In this work, a methodology based on the readily prepared inorganic cyclodiphosph( iii )azane CDA ClP(μ-N t Bu) 2 POBorn (Born = endo -(1 S )-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) is shown to be highly effective in the measurement of ee 's of chiral amines, involving in situ reaction of the chiral amines (R*NH 2 ) with the P-Cl bond of the CDA followed by quaternization of the phosphorus framework with methyl iodide. This results in sharp 31 P NMR signals with distinct chemical shift differences between the diastereomers that are formed, which can be used to obtain the ee directly by integration. Spectroscopic, X-ray structural and DFT studies suggest that the NMR chemical shift differences between diastereomers is steric in origin, with the sharpness of these signals resulting from conformational locking of the bornyl group relative to the P 2 N 2 ring induced by the presence of the P( v )-bonded amino group (R*NH). This study showcases cheap inorganic phosphazane CDAs as simple alternatives to organic variants for the rapid determination of ee . The simple inorganic cyclodiphosph( iii )azane chiral derivatisation agent ClP(μ- t BuN) 2 POBorn (Born = endo -(1 S )-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) is shown to be effective in the measurement of ee 's of chiral amines using 31 P NMR spectroscopy.