Rapid and Stereoselective Access to 6″-Amino-6″-deoxy-α-GalCer Scaffolds

Abstract

This work describes a highly efficient route to an orthogonally protected α-galactosylphytosphingosine (α-GalPhyt) from which 6″-N-modified α-galactosylceramide (α-GalCer) analogues can be synthesized rapidly and on-scale. Key to this route is the use of a d-galactal-derived 1,2-anhydro donor that undergoes an α-selective glycosylation with a sphingoid acceptor. The resulting α-GalPhyt intermediate can be orthogonally deprotected, enabling selective manipulation at either the C-6″ position of the galactose ring or at C-2 of the sphingoid lipid. The utility of this approach was demonstrated by the synthesis of the potent natural killer (NK) T cell agonist, NU-α-GalCer, and a novel 6″-amino-6″-deoxy analogue of another notable agonist, 7DW8–5, both from the same key intermediate.