Zn-Catalyzed Enantio- and Diastereoselective Formal [4 + 2] Cycloaddition Involving Two Electron-Deficient Partners: Asymmetric Synthesis of Piperidines from 1‑Azadienes and Nitro-Alkenes

We
report a catalytic asymmetric synthesis of piperidines through
[4 + 2] cycloaddition of 1-azadienes and nitro-alkenes. The reaction
uses earth abundant Zn as catalyst and is highly diastereo- and regioselective.
A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity
in the process. The presence of ortho substitution
on the arenes adjacent to the bis­(oxazolines) was found to be particularly
impactful, due to limiting the undesired coordination of 1-azadiene
to the Lewis acid and thus allowing the reaction to be carried out
at lower temperature. A series of secondary kinetic isotope effect
studies using a range of ligands implicates a stepwise mechanism for
the transformation, involving an initial Michael-type addition of
the imine to the nitro-alkene followed by a cyclization event. The
stepwise mechanism obviates the electronic requirement inherent to
a concerted mechanism, explaining the successful cycloaddition between
two electron-deficient partners.