Pursuit of Enantioselective Synthesis of Heterocycle-Bearing ­Stereocenters: The Development of a Stereocontrolled BINOL-­Catalyzed Conjugate Addition of Organoboron Nucleophiles

This account chronicles the iterative development of an enantioselective conjugate addition of organoboron nucleophiles to α,β-unsaturated enones and enals catalyzed by BINOL derivatives. Beginning with a specific application of this transformation to the total synthesis of the flinderole alkaloids, the transformation progressed to encompass a much larger scope of heterocycle-substituted electrophiles. The next phase saw progress toward the use of a broader scope of functional nucleophiles, with application in a strategy to synthesize discoipyrrole D. At each stage of this chronologically organized discussion, key problems, hypotheses, and solutions are presented to show the sources of discovery and solutions to problems as the catalyst and other reaction components were made more reactive. The interplay of target-directed reaction development, efforts to increase the scope of compatible functional groups, mechanistic studies, and empirical exploration is described to illustrate sources of chemical discovery.1 Introduction2 Synthesis of the Flinderole Natural Products3 Indole-Bearing Stereocenters4 Heteroaryl-Bearing Stereocenters5 Bis-Heteroaryl Stereocenters6 Synthetic Strategy for Discoipyrrole D7 Bis-Aryl Stereocenters8 Remaining Challenges9 Conclusion