Unexpected Discovery of Saturated Pyridine Mimetics

Abstract

A general approach to 3-azabicyclo[3.1.1]heptanes was unexpectedly discovered. The mechanism, scope, and scalability of this method were studied. The core was incorporated into the structure of the antihistamine drug Rupatidine instead of the pyridine ring, which led to a dramatic improvement in physicochemical properties.

General Synthesis of 3‐Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres**

“…In acetonitrile, dimethyl sulfoxide, and chloroform it was stable even under prolonged heating (entries 21-26). However, in methanol, the isomerization already took place at DFT calculations [16] were performed to rationalize the observed results. A mechanism for ring opening of amine 4 involving only three additional amines (as methylamine) in the proton transfer process is shown in Scheme 5 (model "a").…”

“…A mechanism for ring opening of amine 4 in pure MeOH was finally calculated (model "c") [16] -it was mod-eled with three molecules of methanol. The S N 2-step and proton transfers all happened on a single energy surface with no formal intermediates along the route, an asynchronous concerted reaction (Def2-TZVPP basis).…”

General Synthesis of 3‐Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres**

“…DFT calculations [16] were performed to rationalize the observed results. A mechanism for ring opening of amine 4 involving only three additional amines (as methylamine) in the proton transfer process is shown in Scheme 5 (model "a").…”