Aza-Cope-Mannich 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... 

The prerequisite for an evaluation of the utility of the aza-Cope/ Mannich strategy for a synthesis of strychnine has now been satisfied. Using unsaturated azabicyclo[3.2. ljoctanols closely related to 14, the Overman group had previously demonstrated the impressive facility with which the aza-Cope/Mannich reaction can construct the complex molecular frameworks of ( )-dehydrotubifoline and... 

Scheme 2.198. Domino condensation/aza-Cope/Mannich reaction sequence leading to 2-889.

The highly diastereoselective intramolecular aza-Cope-Mannich reaction was used in the total synthesis of (i)-pancracine (11), an alkaloid natural product5... 

Deng and Overman employed the aza-Cope-Mannich reaction in the enantios-elective total synthesis of (+)-preussin (21), a potent antifungal agent possessing a pyrrolidine skeleton8 (Scheme 1.6h). Conversion of the amino alcohol 22 to the oxazolidine derivative 23 was readily accomplished by reacting with decanal in hot benzene with removal of water using a Dean-Stark trap. Treatment of... 

For a brief review on the aza-Cope-Mannich reaction sequence, see L. Overman, Acc. Chem. Res., 1992,25, 352. 

Consecutive Aza-Cope-Mannich reactions for formation of pyrrolidines with stereo-control (see 1st edition). 

Our initial improvement in the synthesis of pyrrolidine acid 3 relied on a racemic 1,3 dipolar cycloaddition followed by resolution. Attempts to devise asymmetric protocols of this reaction using chiral auxiliaries were not productive. The results from our laboratories were consistent with literature findings, with a moderate diastereoselectivity of 3 to 4 1 at best obtained even when double chiral auxiliaries were used. Several other approaches, such as Aza-Cope/Mannich reaction, intramolecular C-H insertion, and asymmetric aryl 1,4 addition, did not bear fruit. 

This sequence, known as the Aza-Cope/Mannich reaction, has become a synthetically useM method for pyrrolidine synthesis. 

The Overman pyrrolidine synthesis, or aza-Cope-Mannich reaction, was developed while troubleshooting a stereochemical challenge encountered by the Overman group as they pursued the amphibian alkaloid. 

The total synthesis of (-)-strychnine 120 was accomplished using a tandem aza-Cope-Mannich reaction sequence. Amine 115 was exposed to paraformaldehyde to generate 116. This intermediate initiated the aza-Cope reaction to produce 117 and directly underwent the Mannich reaction to ultimately afford 118. Redrawing 118 gives 119 and advanced compound on the way to 120. 

Overall, the first total synthesis of ( + /—)-didehydrostemofoline (52) was carried out in 27 steps from A -terc-butoxycarbonyl-l-hydroxymethyl-3-methoxy pyrrrole with less than 1 % yield featuring a Diels-Alder and an aza-Cope-Mannich reaction as the key transformations in the first preparation of a member of the stemofoline family of Stemona alkaloids possessing the Z configuration of the tetrahydrofuranylidene butenolide substituent. 

The aza-Cope Mannich reaction has observed extensive use in natural product synthesis.One example of its use is in the concise synthesis of the indole alkaloid actinophyl-lic acid 104 (Scheme 17.24). ° Actinophyllic acid was isolated from the leaves of the tree Alstonia actinophylla and shows inhibitory activity toward carboxypeptidase U. Substrate 105 for this sequence is readily obtained from di-tert-butyl malonate in only five steps. Treatment of this material with TFA in CH2CI2 cleaves the A-protecting... 

Agami, C., Cases, M., and Couty, F. (1994) New access to kainoids via a tandem aza-Cope/Mannich reaction. Application to the enantioselective synthesis of (—)-a-allokainic acid. /. Otg. Chem., 59, 7937-7940. 

In contrast to its intermolecular counterpart, an intramolecular Borono-Mannich reaction (Petasis condensation) has been found to proceed with exclusive anti stereoselectivity. The aza-Cope/Mannich reaction has been reviewed. Unprecedented nucleophilic tribromomethylation of Al-t-butanesulfinylimines by bro-moform enables the synthesis of enantiomerically pure a-tribromomethyl amines and 2,2-dibromoaziridines. ... 

A computational and experimental study of the oxy-Cope rearrangement of aldol products has been reported (Scheme 22) and a diastereoselective oxy-Cope/ene/Claisen reaction for the synthesis of decalin frameworks possessing four contiguous stereogenic centres has been applied. The aza-Cope/Mannich reaction has been reviewed. ... 

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