Background Intramolecular Cycloadditions of Indoles

Diels-Alder reaction of the 1,3,4-oxadiazole with the pendant olefin and loss of N2, the C2-C3 7t bond participates in a subsequent 1,3-dipolar cycloaddition with the carbonyl ylide to generate complex polycycles such as 45 as single diastereomers with up to six new stereocenters. That the cascade reaction is initiated by a Diels-Alder reaction with the alkene rather than with the indole is supported by the lack of reaction even under forcing conditions with substrate 46, in which a Diels-Alder reaction with the indole C2-C3 n bond would be required [26a]. 

Rosenmund group never applied this reaction to the Strychnos alkaloids (e.g., akuammicine, 58) is somewhat surprising. 

While we were concerned by the potential problems with our desired reaction, particularly the poor dienophilicity of indoles and the failure of 54 to cyclize under stepwise cyclization conditions, we were nonetheless inspired to pursue this potentially direct strategy. The successes of Marko and Rosenmund in related systems (51 — 52 and 55 — 56, respectively), the ease of substrate synthesis, and the significant utility of the reaction products compelled us to evaluate Zincke 

A particularly interesting aspect of the reaction is its apparent counter-cation dependence. Our initial screen of bases included inorganic bases with a variety of counterions, including Li+, Na+, K+, and MgX+, but only potassium bases were effective. The precise role of the counterion is not completely understood, but it is critical for success. To date, the use of KOf-Bu or KH have consistently provided the best results, with KHMDS used as a lower-yielding alternative if absolutely necessary (in cases where the substrate was unstable to alkoxide bases). 

phosphazine bases, Na2C03, K2C03, Cs2C03, variety of solvents/temperatures NR 

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