Ceramide‐Templated Macrolactams: Total Synthesis and Biological Evaluation of Macrocyclic α‐Galactosylceramide Analogues and their Aglycons

We present the total synthesis of macrocyclic analogues of the immunomodulating glycolipid α‐GalCer (KRN7000), along with the corresponding macrocyclic aglycons. Their structures are inspired by the conformation of α‐GalCer when bound to the antigen presenting glycoprotein CD1d. The applied synthesis plan, involving either ring‐closing metathesis or ruthenium‐catalyzed azide‐alkyne cycloaddition for the crucial macrocyclization step, allowed for easy alteration of the ring size of the macrocycles. These compounds constitute a series of novel cyclic glycosphingolipid analogues. Inspiration from glycoceramides: Based on the conformation of α‐GalCer, when bound to the antigen presenting protein CD1d, a series of novel macrocyclic glycolipid analogues of α‐GalCer has been synthesized. For the key macrocyclization step, either ring‐closing metathesis or azide‐alkyne click chemistry was employed.