Aza-Cope Mannich

Overman s cationic aza-Cope/Mannich strategy is predicated on the observation that the presence of a charged atom in a molecular... 

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.

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. 

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... 

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. 

Racemization of the Mannich ba.se may be caused by intrinsic instability " of the optically active final product, or it may occur during the synthesis or the optical resolution. The former case is fiequently observed in the preparation of cyclic derivatives of natural products and concerns Mannich reactions of different types, including the tandem aza-Cope-Mannich rearrangement, which affords more or less extensively ra-cemized products starting from optically active materials. -" -" - This finding is explained on the basis of the equilibrium involved in the 3,3-reanangement leading to ketones 201 (Fig. 72), key intermediates for the synthesis of alkaloids. 

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. 

Treatment of 192 with acid releases the immonium salt 193 that undergoes the tandem aza-Cope/Mannich sequence. The final product is a single diastereoisomer of the substituted pyrrolidine 195. 

This methodology has been the strategic core of several clever synthetic endeavors carried out by the Overman group. For example, amine 222 was converted into the pentacyclic core of the aspidosperma alkaloid family (Scheme 40) (91JA2598). Condensation of 222 with paraformaldehyde produced oxazoline 223. Heating 223 with excess camphorsulfonic acid (CSA) effected the Aza-Cope/Mannich cyclization cascade to furnish 224 in nearly quantitative yield. 

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

The tandem aza-Cope/Mannich cyclization methodology has been used as a central step in the synthesis of the Amaryllidaceae alkaloid ( + )-crinine starting from 191137. 

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. 

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. 

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