Iminium ion formation/aza-Cope

As expected, some sequences also occur where a domino anionic/pericyclic process is followed by another bond-forming reaction. An example of this is an anionic/per-icyclic/anionic sequence such as the domino iminium ion formation/aza-Cope/ imino aldol (Mannich) process, which has often been used in organic synthesis, especially to construct the pyrrolidine framework. The group of Brummond [450] has recently used this approach to synthesize the core structure 2-885 of the immunosuppressant FR 901483 (2-886) [451] (Scheme 2.197). The process is most likely initiated by the acid-catalyzed formation of the iminium ion 2-882. There follows an aza-Cope rearrangement to produce 2-883, which cyclizes under formation of the aldehyde 2-884. As this compound is rather unstable, it was transformed into the stable acetal 2-885. The proposed intermediate 2-880 is quite unusual as it does not obey Bredf s rule. Recently, this approach was used successfully for a formal total synthesis of FR 901483 2-886 [452]. 

Cooke and coworkers reported on the synthesis of the amino acid N-benzyl-4-acetylproline (2-889) (Scheme 2.198) [453], as this might represent an interesting synthon for the preparation of bioactive compounds. These authors also used a domino iminium ion formation/aza-Cope/Mannich protocol. Thus, treatment of the secondary amine 2-885 with glyoxylic acid (2-888) primarily provided the corresponding iminium ion, which led to 2-889 in 64% yield as a mixture of diastereom-ers. 

Gephyrotoxin (115 a) has been synthesized by Kishi et al. using an approach in which all five asymmetric centres were stereoselectively introduced through hydrogenation reactions. Overman and his co-workers have synthesized per-hydrogephyrotoxin (115b) by a completely different route. The key step is the one-pot conversion of (116) to (117), which proceeds via successive iminium ion formation, aza-Cope rearrangement, and a Mannich reaction. 

On the basis of this rearrangement, an efficient synthetic route to pyrrolidines such as (46) was developed by Overman, starting from oxazolidine (42), via hydroxylated homoallylic imines such as (43 Scheme 22).Mechanistically, the formation of (46) may explained as a tandem-type combination of a cationic aza-Cope rearrangement with a subsequent Maimich cyclization (route a) or, alternatively, as an alkene-iminium ion cyclization/pinacolic rearrangement sequence (route b). 

The presence of certain allylic substituents leads to five-membered ring formation, which proves the occurrence of a fast aza-Cope equilibrium between iminium ions 5 and 6. Such equilibria are possibly also present in the reaction of 1, but do not show up, because both Cope isomers lead to the same cyclization product. Iminium salt 6, however, contains a more nucleophilic double bond, while the electronic bias of the double bond in 6 is such that only five-membered ring formation occurs. 

A process that has been popularized and utilized extensively by Overman and coworkers involves a tandem 2-aza-Cope rearrangement followed by trapping of the resultant isomer by a Mannich reaction. First demonstrated in 1979, this has become a powerful methodology that has found substantial utility in alkaloid synthesis. " The reaction between 215 and benzaldehyde results in formation of iminium ion 217, which undergoes the 2-azonia-Cope rearrangement to give iminium ion 218. Trapping of 218 by the enol functionality results in pyrrolidine 219. 

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