Diastereoselective Synthesis of Nonplanar 3‑Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine

Herein, we report the diastereoselective
synthesis of a 3-amino-1,2,4-oxadiazine
(AOXD) scaffold. The presence of a N–O bond in the ring prevents
the planar geometry of the aromatic system and induces a strong decrease
in the basicity of the guanidine moiety. While DIBAL-H appeared to
be the most efficient reducing agent because it exhibited high diastereoselectivity,
we observed various behaviors of the Mitsunobu reaction on the resulting
β-aminoalcohol, leading to either inversion or retention of
the configuration depending on the steric hindrance in the vicinity
of the hydroxy group. The physicochemical properties (pKa and log D) and hepatic stability of
several AOXD derivatives were experimentally determined and found
that the AOXD scaffold possesses promising properties for drug development.
Moreover, we synthesized alchornedine, the only natural product with
the AOXD scaffold. Based on a comparison of the analytical data, we
found that the reported structure of alchornedine was incorrect and
hypothesized a new one.