Practical Alkaloid Synthesis on the axis of Asymmetric Azaelectrocyclization

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Substituted piperidines can be regarded as a core structure of many naturally occurring alkaloids, including indol alkaloids. Furthermore, these functionalized six-member nitrogen heterocycles have drawn a great deal of attention because of their attractive pharmacological activities. Thus, the stereo-controlled synthesis of piperidines with various substitution patterns is one of the current topics for many synthetic chemists. Recently, we established the highly stereoselective asymmetric 6π-azaelectrocyclization of conformationally flexible linear 1-azatrienes using 7-alkyl-substituted cis-aminoindanol derivatives. Our asymmetric azaelectrocyclization is based on the discovery that the remarkable frontier-orbital interaction between the HOMO and LUMO of the 1-azatrienes significantly accelerates the azaelectrocyclization in the presence of C4-carbonyl and C6-alkenyl or aryl substituents. In order to establish our asymmetric 6π-azaelectrocyclization toward a new strategy for alkaloid … More synthesis, we succeeded the following fruitful results in this project : (1)The stereoselective synthesis of chiral 2,4,6-trisubstituted piperidines was achieved by an efficient one-pot procedure of asymmetric the 6π-azaelectrocyclization resulting from mixing vinylstannan possessing various unsaturated groups, vinyl iodides having both aldehyde and ester groups, and the cis-aminoindanol derivative of the chiral nitrogen source in the presence of Pd(0) catalyst. (2)The method was successfully applied to the synthesis of an indolidizine alkaloid, (-)-dendroprimine, a simple but a challenging molecule for the stereoselective construction of three stereogenic centers on a small piperidine skeleton. (3)The stereo-controlled construction of the 2,4,5,6-tetrasubsituted piperidine derivatives toward synthesis of indol alkaloids was successfully realized by the asymmetric azaelectrocyclization of indol derivatives. (4)Asymmetric stereocontrolled total synthesis of (-)-corynantheidol, an indol alkaloid, was achieved by utilizing the 2,4,5,6-tertasubstituted piperidine construction method described above, followed by one-carbon elongation, cleavage of the indanol group, the C ring construction by the Pummerer reaction, and then functional group manipulations. Less