Biaryls represent a major area of natural and unnatural products chemistry. Given the widespread occurrence of physiologically active compounds in Nature that contain a biaryl axis, many of which due to hindered rotation possess an element of axial chirality, methodology is needed to respond to these special synthetic challenges. Representative targets which highlight existing limitations yet which provide opportunities for significant advances in this area include the clinically essential antibiotic vancomycin, and the potent anti-AIDS biaryls, the michellamines. Using a judiciously placed internal phosphine ligand in an aryl halide coupling partner, the directionality associated with our key Suzuki-biaryl coupling-based approach to the vancomycin biaryl and the subunits of the michellamines will be controlled. Alternatively, a conceptually new entry to stereocontrolled biaryls, as applied to vancomycin, will be pursued using a Bergman cyclization of a substituted nonracemic endiyne. The chemistry of biaryl constructions, which is usually effected in solution using Pd(0) catalysis, is to be pursued via an alternative metal system: nickel. Proposed herein are new methods for heterogeneous catalysis based on Ni/C, to be examined under microwave conditions, and the next generation species nickel-on-graphite (""""""""Ni/Cg""""""""), which appears to offer a different reactivity profile. Finally, a new series of nonracemic ligands based on the binaphthyl core, in particular of NOBIN, will be constructed. The approach presented will provide entry to unprecedented substitution patterns on this ligand system, as well as opportunities for their mounting on a solid support for use, and re-use, under heterogeneous conditions. A particular, albeit representative, application of a novel substituted cyclo-NOBIN will be studied for selected asymmetric aldol reactions.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
Zip Code
Handa, Sachin; Lippincott, Daniel J; Aue, Donald H et al. (2014) Asymmetric gold-catalyzed lactonizations in water at room temperature. Angew Chem Int Ed Engl 53:10658-62
Lipshutz, Bruce H; Amorelli, Benjamin (2009) Total synthesis of piericidin A1. Application of a modified Negishi carboalumination-nickel-catalyzed cross-coupling. J Am Chem Soc 131:1396-7
Butler, Tom A; Swift, Elizabeth C; Lipshutz, Bruce H (2008) Heterogeneous catalysis with nickel-on-graphite (Ni/Cg). Org Biomol Chem 6:19-25
Lipshutz, Bruce H; Butler, Tom; Swift, Elizabeth (2008) C-C bond formation catalyzed heterogeneously by nickel-on-graphite (Ni/Cg). Org Lett 10:697-700
Lipshutz, Bruce H; Frieman, Bryan A; Lee, Ching-Tien et al. (2006) Microwave-assisted heterogeneous cross-coupling reactions catalyzed by nickel-in-charcoal (Ni/C). Chem Asian J 1:417-29
Lipshutz, Bruce H; Frieman, Bryan A; Butler, Tom et al. (2006) Heterogeneous catalysis with nickel-on-graphite (Ni/C(g)): reduction of aryl tosylates and mesylates. Angew Chem Int Ed Engl 45:800-3
Tasler, Stefan; Lipshutz, Bruce H (2003) Nickel-on-charcoal-catalyzed aromatic aminations and Kumada couplings: mechanistic and synthetic aspects. J Org Chem 68:1190-9
Lipshutz, Bruce H; Tasler, Stefan; Chrisman, Will et al. (2003) On the nature of the 'heterogeneous' catalyst: nickel-on-charcoal. J Org Chem 68:1177-89
Bringmann, Gerhard; Menche, Dirk; Muhlbacher, Jorg et al. (2002) On the verge of axial chirality: atroposelective synthesis of the AB-biaryl fragment of vancomycin. Org Lett 4:2833-6
Lipshutz, B H; Blomgren, P A (2001) Efficient scavenging of Ph3P and Ph3P=O with high-loading merrifield resin. Org Lett 3:1869-71