New Regio- and Stereo­selective Cascades via Unstabilized Azomethine Ylide Cycloadditions for the Synthesis of Highly Substituted Tropane and Indolizidine Frameworks

Multisubstituted tropanes and indolizidines have been prepared with high regio- and stereo­selectivity by the [3+2] cycloaddition of unstabilized azo­methine ylides generated from readily prepared trimethylsilyl-substituted 1,2-dihydro­pyridines via protonation or alkylation followed by desilylation. Starting from 1,2-dihydro­pyridines bearing a ring trimethylsilyl substituent at the 6-position, an intermolecular alkylation/desilylation provides endocyclic unstabilized ylides that successfully undergo cycloaddition with a range of symmetrical and unsymmetrical alkyne and alkene dipolarophiles to afford densely substituted tropanes incorporating quaternary carbons in good yields and with high regio- and stereo­selectivity. Additionally, an intramolecular alkylation/desilylation/cycloaddition sequence provides convenient and rapid entry to bridged tricyclic tropane skeletons, allowing for five contiguous carbon stereocenters to be set in a single experimental operation and under mild conditions. Starting from 1,2-dihydro­pyridines with trimethyl­silyl­methyl groups on nitrogen, protonation followed by desilylation generates exocyclic unstabilized ylides that undergo cycloaddition with unsymmetrical alkynes to give indolizidines with good regio- and stereo­selectivity. N-Trimethylsilylmethyl-1,2-dihydro­pyridines can also be alkylated and subsequently desilylated to give endocyclic unstabilized ylides that undergo intermolecular cycloadditions with carbonyl compounds to give bicyclic oxazolidine products in good overall yields. Moreover, an intramolecular alkylation/desilylation/cycloaddition sequence with the N-trimethyl­silyl­methyl-1,2-dihydro­pyridines affords tricyclic indolizidines that incorporate quaternary carbons and up to five stereocenters with good to excellent regio- and diastereo­selectivity.