Enantioenriched Methylene‐Bridged Benzazocanes Synthesis by Organocatalytic and Superacid Activations

Abstract

Achieving in a straightforward way the synthesis of enantioenriched elaborated three‐dimensional molecules related to bioactive natural products remains a long‐standing quest in organic synthesis. Enantioselective organocatalysis potentially offers a unique opportunity to solve this problem, especially when combined with complementary modes of activation. Here, we report the sequential association of organocatalytic and superacid activations of simple linear achiral readily available precursors to promote the formation of unique highly elaborated chiral methylene‐bridged benzazocanes exhibiting three to five fully‐controlled stereocenters. This peculiar backbone, difficult to assemble by standard synthetic approaches, is closely related to bioactive natural and synthetic morphinans and benzomorphans. The formation of a highly reactive chiral 7‐membered ring N‐acyl iminium superelectrophilic ion, evidenced by low‐temperature in situ NMR experiments, triggers a challenging stereoselective Friedel–Crafts‐type cyclization.

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

“…The feasibility of the reaction was assessed using oxa‐bridged azepane 1 a , [7] which was subjected to superacid activation [12] using triflic acid (TfOH) (Table 1). We were pleased to observe the clean formation of the tricyclic azepane 4 a via a chemoselective 6‐ endo ‐ trig arylation in an excellent yield (98 %), and modest control of the diastereoselectivity (Table 1, entry 1, dr=3.5 : 1).…”

“…Synthetic methodologies aimed at the functionalization of optically‐active heptacyclic NAIs are limited to only few reports, generally starting from the chiral pool, and necessitate several steps [6] . On the basis of our recent interest in the combination of organocascades with superacid activation for the access to medium‐sized ring heterocycles 3 , [7] we devise that oxa‐bridged azepane 1 , obtained in one domino reaction from easily available starting materials, [8] could act as a hidden chiral enantioenriched heptacyclic NAI 2 under superacid activation. By a careful design of substrates 1 , concerning the nature of the appended aromatic nucleophilic substituents (Ar 1 , Ar 2 ), directed chemo‐ and diastereoselective intramolecular arylations can be expected delivering either enantioenriched fused‐tricyclic azepanes 4 or bridged‐polycyclic azocanes 5 (Scheme 1B).…”

Enantioselective Organocatalysis and Superacid Activation: Challenges and Opportunities

“…The activated oxa‐bridged azepane intermediate acts as a key hidden heptacyclic chiral N ‐acyl iminium ion 2 triggering a chemo‐ and diastereoselective intramolecular mono‐ or di‐arylation. 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] .…”

Asymmetric Aldol “Reaction in Water” Using Ferrocene-Amino Acid Conjugates

“…Enantiomerically pure molecules are valuable building blocks for the manufacture of a plethora of pharmaceutical compounds and agrochemicals. 1 They are produced from simple, cheap, and easily available prochiral substrates using chiral catalysts. 2 Enzymes are the exquisite example of chiral catalysts.…”

“…The reaction was carried out at an ambient temperature for 24 h, giving the R-and S-isomers of 4hydroxy-4-(4-nitrophenyl)butan-2-one. The conversion and enantiomeric excess (ee) of the aldol products were estimated by 1 H NMR, Figures S48−S54, and HPLC-UV analyses, Figures 4 and S55.…”