Direct Access to Tetrasubstituted Cyclopentenyl Scaffolds through Diastereoselective Isocyanide-based Multicomponent Reaction

An efficient strategy combining the stereocontrol of organocatalysis with the diversity-generating character of multicomponent reactions is described to produce structurally unique, tetrasubstituted cyclopentenyl frameworks. An asymmetric Michael addition-hemiacetalization between α-cyanoketones and α,β-unsaturated aliphatic aldehydes was implemented for constructing cyclic hemiacetals, which were next employed as chiral bifunctional substrates in a new diastereoselective intramolecular isocyanide-based multicomponent reaction. This approach furnished a diversity of structurally complex compounds – including peptidomimetics and natural product hybrids in high stereoselectivity (up to 97% ee and up to >99:1 dr) and in moderate to high yields.