Synthesis of 2‐Aza‐Bicyclo[4.3.0]nonane Derivatives Related to the Camporidines via Intramolecular [3+2]‐Cycloaddition

Studies toward the total synthesis of the piperidine alkaloid camporidine A are reported. The core ring system was established through intramolecular nitrile oxide olefin cycloaddition, while the precursors were assembled by Ir‐catalyzed asymmetric allylic amination in the presence of a chiral phosphoramidite ligand and subsequent Ru‐catalyzed ring‐closing metathesis. Using model compounds lacking the hexyl sidechain, we demonstrated that a 2‐aza‐bicyclo‐[4.3.0]nona‐5‐en‐7‐one intermediate, obtained from the isoxazoline cycloadduct by Raney–Nickel reduction, imine hydrolysis, and elimination, can be diastereoselectively epoxidized and further converted to camporidine analogs by Nicolaou–Baran dehydrogenation or E ‐selective Wittig olefination. A related sequence was realized with n ‐hexyl substituted compounds employing 2‐vinyl‐octylamine (98% ee), prepared by enantioselective allylation of ethyl nitroacetate and subsequent Krapcho decarboxylation and reduction. However, the epoxidation step failed in this case. An alternative route toward compounds displaying the core ring system of the target compounds started with the addition of 2‐(1,3‐dioxolan‐2‐yl)ethyl magnesium bromide to N‐methoxycarbonyl‐3‐(tri‐ iso‐ propylsilyl)pyridinium chloride to give a 1,2‐dihydropyridine derivative. Surprisingly, upon reaction of the acetal with hydroxylamine, the oxime intermediate directly underwent a formal intramolecular oxime olefin cycloaddition, which according to DFT calculations proceeded as a two‐step process. The resulting isoxazolidine was further transformed via bromo‐desilylation and Suzuki coupling to hexyl‐substituted derivatives.