Strychnine cascade reactions

In 2010, Reissig and coworkers demonstrated the power of Sml2-induced cascade reactions in a formal total synthesis of strychnine (Scheme 13.14) [16], starting from... 

Scheme 13.14 Formal total synthesis of strychnine (100) by using a Smij-induced cascade reaction.

Beemelmanns, C., Reissig, H. (2010). A short formal total synthesis of strychnine with a samarium diiodide induced cascade reaction as the key step. Angewandte Chemie International Edition, 49, 8021-8025. 

To demonstrate the power of these cascade sequences this methodology was successfully applied to total syntheses of several indole-derived alkaloids, for example, minfiensine [113]. By implementation of organocatalyzed cascade reactions the MacMillan group was able to dramatically reduce the number of reaction steps in total syntheses of strychnine, aspidospermidine, and kopsinine [114]. 

Professor Larry E. Overman first reported the titled reaction as a young member of the University of California, Irvine faculty. Since his initial report in 1979, the Overman group has used this cascade approach to a variety of natural products, including (+)-strychnine, (-)-pancracine, and ( )-gelsemine. ... 

Very recently, Padwa reported a total synthesis of strychnine based on an intramolecular Diels-Alder reaction/rearrangement cascade, which was previously developed in his group to assemble the tetracyclic core ring system of indole alkaloids (Scheme 16) (174-178). Intramolecular cycloaddition reactions often benefit from higher reactivity and greater control of stereoselectivity relative to their intermolecular counterparts. Unlike Bodwell s lEDDA reaction (Scheme 13), the reaction of an electron-rich furan moiety with an N-acyl indole moiety required only a single tether. His synthesis also involved... 

The cycloaddition/rearrangement IMDAF cascade of 2-amidofurans such as 319 was remarkably efficient given that two heteroaromatic systems are compromised in the reaction. Closure of 321 to the remaining D-ring of the Strychnos skeleton (i.e., 322) was carried out from the aza-tetracyclic intermediate 321 by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the A-tethered vinyl iodide and the keto functionality. The cycloaddition/rearrangement approach was successfully applied to a synthesis of the heptacyclic fi-amework of ( )-strychnine 323 (Scheme 13.72) [114], which required only 13 steps from furanyl indole 319 and proceeded in an overall yield of 4.4%. 

An interesting transannular Diels-Alder/retro-Diels-Alder reaction cascade was employed in a formal total synthesis of ( )-strychnine by Bodwell and Li (Scheme 20.5). ° The reaction cascade involved a transannular inverse-electron-demand Diels-Alder (lEDDA) reaction of cyclophane 12 to form 13, which spontaneously expelled a molecule of nitrogen by the retro-Diels-Alder reaction to give 14 in quantitative yield. This led to a formal total synthesis of strychnine after 14 was converted into a common... 

SCHEME 20.5. The transannular Diels-Alder/retro-Diels-Alder reaction cascade in the synthesis of ( )-strychnine. 

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