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

Abstract

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 Introduction

2 Synthesis of the Flinderole Natural Products

3 Indole-Bearing Stereocenters

4 Heteroaryl-Bearing Stereocenters

5 Bis-Heteroaryl Stereocenters

6 Synthetic Strategy for Discoipyrrole D

7 Bis-Aryl Stereocenters

8 Remaining Challenges

9 Conclusion

Key words

heterocycles - organocatalysis - natural product total synthesis - conjugate addition - BINOL catalysis - heteroaryl stereocenters

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• 1 Current affiliation: Faculty of Applied Sciences, Ton Duc Thang University, 19 Nguyen Huu Tho, Tan Phong Ward, District 7, Ho Chi Minh City, Vietnam 70000.
• 2 Current affiliation: Biochemistry Department, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
• 3 Current affiliation: Sciegen Pharmaceuticals, 89 Arkay Drive, Hauppauge, NY 11788, USA.
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