Bridgehead iminium ion

The tandem cationic aza-Cope rearrangement followed by a Mannich cyclization was applied in the synthesis of the novel tricyclic core structure of the powerful immunosupressant FR901483 in the laboratory of K. Brummond. Their approach was the first synthetic example in which this tandem reaction passes through a bridgehead iminium ion. 

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. 

Scheme 12.39 First cinchona cage expansion of quincorine and quincoridine. Distinct bridgehead iminium ions 109 + and 110+ and their stereospecific capture by nucleophiles.

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... 

Entry 4 involves nitrogen participation and formation of an iminium ion that is reduced by NaBH4. The reaction in Entry 5 creates an 11-methylenebicyclo[4.3.1]undecen-3-one structure found in a biologically active natural product. Note that this fragmentation creates a bridgehead double bond. Entry 6 involves construction of a portion of the taxol structure. The reaction in Entry 7 is stereospecific, leading to the E-double bond. 

Kibayashi s approach from bridgehead azabicyclic iminium ions... 

In 1997 Kibayashi reported the first approach to the tricyclic framework of FR901483 [11] based on the synthesis of l-alkyl-2-azabicyclo[3.3.1]-nonanes (e.g. IX), as depicted in Scheme 30, through a nucleophilic bridgehead alkylation on an anti-Bredt iminium ion (e.g. VIII), which is available by means of the Lewis acid-induced cleavage of tricyclic N,0-acetals (e.g. VII). 

The iminium-ion-induced process allows access to additional transition-state conformations relative to Wienreb s JV-acyl imine methodology, since transition-state constraints imposed by the /V-acyl group are absent. Therefore, the different aza Diels-Alder protocols provide methodological alternatives for controlling the stereochemical outcome in the synthesis of alkaloids embodying a bridgehead nitrogen. 

When quinamine was refluxed in dilute acetic acid for a prolonged period it afforded the ketoamine, quinamicine, which may have been the result of a direct loss of water or more likely an allylic rearrangement of the tertiary hydroxyl group in the hydroxy-methyleneindoline form then elimination (the hydroxyl cannot be lost to form the iminium ion because of the bridgehead position of the quinuclidine nitrogen). The formulation of quinamicine is the only reaction of these compounds which has any parallel in... 

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