Aza-Cope rearrangement-Mannich cyclization reaction

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

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. 

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-... 

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

The aza-Cope/Mannich reaction takes advantage of the facility with which a y,<5-unsaturated itninium ion, such as 6, participates in a [3,3] sigmatropic rearrangement to give an isomeric species which is suitably functionalized for an intramolecular and irreversible Mannich cyclization (see intermediate 7). The aza-Cope rearrangement substrate 6 is simply an unsaturated iminium ion which can be fashioned in a number of ways from a homoallylic... 

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]. 

The use of a cationic aza-Cope rearrangement in concert with a Mannich cyclization has also been applied to the total synthesis of enantiomerically pure (—)-crinine (359) (205). In the event, nucleophilic opening of cyclopentenoxide with the aluminum amide that was formed on reaction of (/ )-a-methylbenzyl-amine and trimethylaluminum gave the amino alcohol 485 together with its (15,25) diastereomer. Although there was essentially no asymmetric induction in this process, the diastereomeric amino alcohols were readily separated by chromatography, and the overall procedure therefore constitutes an efficient means for the preparation of enantiomerically pure 2-amino alcohols from epoxides. When the hydrochloride salt derived from 485 was treated with paraformaldehyde and potassium cyanide, the amino nitrile 486 was formed. Subsequent Swem oxida-... 

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. 

The landem aza-Cope/Mannich cyclization reaction has also been used in the synthesis of enantiomerically pure tx-amino acid derivatives, e.g., proline derivative 741l49. Thus, the rearrangement of intermediate 70, derived from 69 and glyoxal by acid treatment, produces a 1 1 mixture of 72 and the head-to-tail self-condensation product 73, which can be transformed to 72 by subsequent acid treatment. 

To control the equilibrium position of the rearrangement, Overman and others introduced a nucleophilic hydroxyl group at the C2 position to capture the rearranged iminium ion2 (Scheme 1.6b). Although the levels of diastereoselecti-vity for the formation of pyrrolidines 6a and 6b are low, the tandem cationic aza-Cope-Mannich cyclization provides a variety of substituted 3-acylpyrrolidines in high yields under mild reaction conditions. The first step in the reaction is the... 

---