Aza-Cope-Mannich rearrangement

Deng and Overman [74] employed their aza-Cope rearrangement-Mannich cyclization reaction as the key step in an approach to both (+)-and (-)-preussin. 

Overman, L. E. Kakimoto, M. Okazaki, M. E. Meier, G. P. Carbon-carbon bond formation under mild conditions via tandem cationic aza-Cope rearrangement-Mannich reactions. 

During the enantioselective total syntheses of (-)- and (+)-strychnine and the Wieland-Gumlich aldehyde, L.E. Overman and co-workers used the tandem aza-Cope rearrangement/Mannich reaction as a key step. This central aza-Cope/Mannich reorganization step proceeded in 98% yield. 

Jacobsen, E. J., Levin, J., Overman, L. E. Synthesis applications of cationic aza-Cope rearrangements. Part 18. Scope and mechanism of tandem cationic aza-Cope rearrangement-Mannich cyclization reactions. J. Am. Chem. Soc. 1988, 110, 4329-4336. 

Brummond, K. M., Lu, J. Tandem Cationic aza-Cope Rearrangement-Mannich Cyclization Approach to the Core Structure of FR901483 via a Bridgehead Iminium Ion. Org. Lett. 2001, 3,1347-1349. 

One of the most original and ingenious routes to the synthesis of the aspidospermine alkaloids is the tandem aza-Cope rearrangement-Mannich cyclization route developed by Overman and collaborators. This was originally introduced in a synthesis of 11-methoxytabersonine (q.v.), and it has also been applied to the synthesis of deoxylimapodine (479) and N-acetylaspidoalbidine (480) (308). This work has already been discussed in an earlier volume (4), to which the reader is referred for details. 

Perhaps the best illustration of the utility of tandem aza-Cope rearrangement-Mannich cyclization reactions for assembling complex molecular skeletons is found in the total synthesis of the Aspidosperma alkaloid ( )-16-methoxytabersonine (Scheme 56).115 The crucial step in this synthesis was the high-yielding conversion of aniline (156) to 16-methoxy-l,2,6,7-tetradehydroaspidospermidine (157), a trans-... 

Homoallylic amines containing an allylic hydroxy group rearrange in the presence of an aldehyde and an acid catalyst to yield 3-acylpyrrolidines. If the starting amino alcohol is cyclic, this transformation provides a pyrrolidine-annulated product, in which the initial ring is expanded by one member. The mechanism has been proposed to proceed via a tandem cationic aza-Cope rearrangement/Mannich cyclization1134. 

The tandem aza-Cope rearrangement/Mannich cyclization of substrate 30 is the key step in the stereocontrolled total synthesis of the Strychnos alkaloid (+)-dehydrotubifoline (31)1140, and rearrangement of precursor 32 is the central step in the enantioselective total synthesis of (— )-strychnine1141. 

Brummond s synthesis through the tandem cationic aza-Cope rearrangement-Mannich cyclization reaction... 

Brummond s approach to FR901483 involves compound V, which can be accessed in a very efficient manner using a tandem cationic aza-Cope rearrangement/Mannich cyclization strategy. The complete retrosynthetic analysis leads to three relatively simple starting materials (Scheme 25). 

Overman and co-workers continue to report new applications of their tandem cationic aza-Cope rearrangement-Mannich cyclization route to nitrogen heterocyclic systems. Perhaps the nicest illus-... 

Other academic groups have used the Overman pyrrolidine synthesis en route to complex alkaloids and other medicinally relevant compounds. The Brummond group at the University of Pittsburgh has reported the formal synthesis of (-)-FR901483 (48), an immunosuppressant isolated by researchers at Fujisawa Pharmaceuticals. In this report, Brummond incorporated a tandem cationic aza-Cope rearrangement/Mannich cyclization that proceeds via a bridgehead iminium ion. Treatment of intermediate 44... 

One of the more impressive demonstrations of this reaction was in the landmark total synthesis of strychnine by Overman and coworkers. Treatment of 220 with formaldehyde resulted in an iminium ion which underwent the tandem 2-aza-Cope rearrangement/Mannich sequence to give 221 which was elaborated to (-)-strychnine in six more steps. 

---