An unexpected reaction pathway in the synthesis of the ABCE framework of strychnine-type alkaloids – A multidisciplinary study

• Unexpected imino-Diels-Alder reaction in aza-Prins conditions of a spiro-derivative.
• Resulting polyheterocyclic structure solved using residual dipolar couplings.
• Retro-imino-Diels-Alder reaction observed and monitored long-term by NMR.
• Instability of the polyheterocycle exploited in the synthesis of 6-5-5-5 tetracycles.
• Relative configuration of the formed tetracyclic framework proven by X-ray.

Acid-catalyzed cyclization of spirocyclic 1′-benzyl-2′-(prop-2-en-1-yl)spiro[indole-3,3′-pyrrolidine]-5′-one (1) was performed. The pentacyclic product of Povarov-like imino-Diels-Alder reaction was isolated in high yield instead of expected tetracyclic aza-Prins intermediate. The unusual exotic alkaloid-type structure of the resulting molecule 2 was unambiguously confirmed by a detailed NMR analysis using a set of 2D NMR spectra including an INADEQUATE experiment. The relative configuration of 2 was predicted from the synthesis mechanism and DFT geometry calculations and independently confirmed using NOESY and residual dipolar coupling (RDC) assisted NMR analysis in stretched crosslinked polystyrene gels. The reversibility of the cycloaddition in aprotic solvents was observed. A new reaction pathway yielding a rare 6-5-5-5 tetracyclic spiroindoline 3 was suggested. The relative configuration within the tetracyclic framework was ultimately proved using Single-crystal X-ray diffraction analysis of compound 4.

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