Hidden Heptacyclic Chiral N‐Acyl Iminium Ions: A New Entry to Enantioenriched Polycyclic Azepanes and Azocanes by Superacid‐Promoted Intramolecular Pictet‐Spengler Reaction

Abstract

Enantioenriched complex fused‐tricyclic azepanes or bridged‐polycyclic azocanes were constructed via a two‐step sequence involving an enantioselective organocascade followed by superacid activation of the domino adduct. The activated oxa‐bridged azepane acts as a key hidden heptacyclic chiral N‐acyl iminium ion triggering a chemo‐ and diastereoselective intramolecular mono‐ or di‐arylation.

Enantioselective Organocatalysis and Superacid Activation: Challenges and Opportunities

“…By careful choice of the Ar 1 , Ar 2 and n, the superacid‐promoted intramolecular Pictet–Spengler [45] reaction can involve Ar 1 , generating optically‐enriched methylene‐bridged benzazocanes 3 closely related to bioactive morphinan and benzomorphan scaffolds [46] . Alternatively, the cyclization can also involve Ar 2 to afford the enantioenriched pyrido[1,2‐a]azepane ring system 4 , [47] which is found in many biologically relevant molecules, such as banistenoside A and B [48] . Finally, a cascade cyclization involving successively Ar 1 and Ar 2 was found possible to give the complex fused‐polycyclic azocanes 5 .…”

Automated exploration of the conformational degrees of freedom along reaction profiles - driving a FASTCAR

“…The first example involves a Diels-Alder reaction between 4,4-dimethyl-3-methylenepent-1-ene (1) and (E)-dec-5-ene (2), which has a total of 6,561 potential conformers due to eight rotatable bonds. The second example involves an intramolecular acidcatalysed cyclization reaction of polycyclic azocane derivative, a previously analyzed reaction in our group 9 and whose selectivity appeared to be driven by conformation equilibria. The third example relies on an enantioselective organo-catalysed rearrangement of benzofurane derivatives (Black rearrangement), where selectivity was assumed to relate to differences in steric repulsion in the two putative transition state geometries.…”