Femtoreview: Carbonyl ylide cycloadditions in the synthesis of aspidosperma alkaloids

Aspidosperma alkaloids are challenging targets in natural product synthesis due to the complexity of their tightly fused polycyclic core scaffold. Intramolecular cycloadditions in carbonyl ylide intermediates have proven to be powerful transformations in accessing these structures.

Albert Padwa and co-workers have published two reports regarding the synthesis of the central core of the aspidosperma alkaloids.1 Their approach utilises Rh(II)-catalysed carbenoid chemistry. In the presence of a Rh(II) catalyst, the substrate undergoes a cyclising intramolecular carbonyl ylide formation with the proximal amide carbonyl. This is subsequently trapped by an intramolecular dipolar cycloaddition forming the central apsidosperma alkaloid core. This intermediate compound was taken forward to the natural product vindoline.

More recently, Boger and co-workers have reported a divergent approach for the total synthesis of (-)-Aspidospermine and (+)-Spegazzinine.2 Their approach also involves a carbonyl ylide intermediate, formed in this instance from an oxadiazole precursor by [4+2] cycloaddition and expulsion of N2, which undergoes an intramolecular [3+2] cycloaddition to provide the central aspidosperma alkaloid core.

Both approaches demonstrate the complexity that can be generated with stereocontrol through the use of carbonyl ylides in intramolecular cycloadditions.

1. (a) Padwa et al., J. Org. Chem., 1995, 60, 6258, (b) Padwa et al., J. Org. Chem., 1998, 63, 556.
2. Boger et al., Org. Lett., 2012, 14, 2078.


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