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Review | Regular issue | Vol 87, No. 4, 2013, pp.729-761
Published online, 26th February, 2013
DOI: 10.3987/REV-12-761
One-Pot Asymmetric 6π-Azaelectrocyclization as a New Strategy for Alkaloid Synthesis

Toyoharu Kobayashi, Taku Sakaguchi, and Shigeo Katsumura*

*Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan

Abstract

The one-pot asymmetric 6π-azaelectrocyclization of alkenyl vinyl stannane, ethyl (Z)-2-iodo-4-oxobutenoate, and (–)-7-isopropyl-cis-aminoindanol in the presence of a Pd(0) catalyst stereoselectively produced the tetracyclic aminal compounds, resulting from the four-bond formation by controlling the stereochemistry at the two created asymmetric centers. This asymmetric one-pot protocol was developed based on the studies of the previously established asymmetric azaelectrocyclization, and the produced cyclic aminals can be regarded as synthetic precursors of 2,4-disubstituted chiral piperidines. Furthermore, we also developed a new version of the one-pot asymmetric 6π-azaelectrocyclization using t-butyl (Z)-3-formyl-2-iodopentenoate instead of ethyl (Z)-2-iodo-4-oxobutenoate, which directly afforded the precursors of the 2,4,5-trisubstituted piperidines. The syntheses of the 2,4- and 2,4,5-substituted piperidines were realized by the chemoselective reduction of the conjugated double bond to the ester group in the one-pot azaelectrocyclization products. The synthesis of the 2,4,6-trisubstituted piperidines was achieved by the stereocontrolled alkylation of the aminal moiety in the resulting cyclized products as a key step. The 2,3,4-trisubstituted piperidines were also synthesized utilizing the stereoselective 1,4-addition reaction of the unsaturated ester with a Grignard reagent resulting from the novel neighboring group participation. By applying this protocol, the total syntheses of (–)-dendroprimine, an indolizidine alkaloid, containing the 2,4,6-trisubstituted piperidine motif and (–)-20-epiuleine, a strychnos-type indole alkaloid, containing the 2,3,4-trisubstituted piperidine motif, were achieved.