Indolizidines Mannich reaction

Tethering the alkene to the carbon atom of the nitrone allows the preparation of cw-l,2-disubstituted cycloalkanes such as 212. Examples in which the alkene is tethered to the nitrogen atom of the nitrone are also common. Thus, addition of formaldehyde to the hydroxylamine 213 promoted formation of the intermediate nitrone and hence the cycloadduct 214 (3.140). " Subsequent transformations led to the alkaloid luciduline. This synthesis illustrates a useful feature of the 1,3-dipolar cycloaddition reaction of nitrones, in that it provides an alternative to the Mannich reaction as a route to (3-amino-ketones, via reductive cleavage of the N-0 bond in the isoxazolidine and oxidation of the 1,3-amino-alcohol product. In another example of such an intramolecular cycloaddition reaction, the bridged bicyclic product 217, used in a synthesis of indolizidine 209B, was formed by addition of an aldehyde to the hydroxylamine 215, followed by heating the intermediate nitrone 216 (3.141).142... 

Based on the Br0nsted add-catalyzed asymmetric vinylogous Mannich reaction, the lab of Schneider developed a highly flexible approach to access a variety of naturally and nonnaturally occurring indolizidine alkaloids, in general, in 11 steps in overall yields exceeding 36% (Scheme 11.52)... 

SCHEME 11.52 A flexible approach toward the total synthesis of various indolizidine alkaloids based on the asymmetric vinylogous Mannich reaction as key step. 

A sequence of tandem-Mannich-Michael reactions and conjugate additions of organocuprates has been used for the synthesis of enantiomerically pure alkaloids such as (—)-dihydro-pinidine 193, the indolizidine alkaloid (5/, 8a/ )-gephyrotoxin 167B 194 and the decahydroquinoline alkaloid 4a- p/-pumiliotoxin C 195 (Figure 10.18) [150]. 

Weymann, M, Pfrengle, W, Schollmeyer, D, Kunz, H, Enantioselective syntheses of 2-alkyl, 2,6-dialkylpiperidines and indolizidine alkaloids through diastereoselective Mannich-Michael reactions, Synthesis, 1151-1160, 1997. 

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