A Catalytic Asymmetric Synthesis of Polysubstituted Piperidines Using a Rhodium(I)-Catalyzed ~(2+)~(2+)2 Cycloaddition Employing a Cleavable Tether

摘要

Due to their prevalence in drug targets and natural products, the asymmetric synthesis of nitrogen-containing heterocycles is an important focus of the synthetic community. Our group has a longstanding interest in the catalytic asymmetric synthesis of such moieties (Scheme 1). In 2006, we reported the rhodium(I)-catalyzed asymmetric 2+2+2 cycloaddition between alkenyl isocyanates and alkynes. This catalytic, asymmetric method allows facile access to indolizidines and quinolizidines, important scaffolds in natural products and pharmaceutical targets, in good yields with high enantiose-lectivities, Extension of this methodology to the synthesis of monocyclic nitrogen-containing heterocycles would be useful, as piperidines are present in numerous compounds with interesting biological activities, such as alkaloid 241D, isosolenopsin Aand palinavir (Figure 1). Recently, several new methods have been reported for the synthesis of polysubstituted piperidines, highlighted by Bergman and Ellman's recent contribution.Catalytic asymmetric approaches to polysubstituted piperidines, however, remain scarce with the notable exception of the powerful aza-Diels-Alder reaction.Complementary approaches to piperidines relying on the union of two or more fragments with concomitant control of stereochemistry in the process would be of significant value.Herein, we report a partial solution to this problem relying on an asymmetric rhodium-catalyzed cycloaddition of an alkyne, alkene and isocyanate, bringing three components together wherein two of the three are attached by a removal linker.