Lithium amides are some of the most important reagents in organic synthesis. The pharmaceutical industry uses these reagents frequently and on very large scales. In this proposal we describe efforts to understand the underlying chemistry of the most important reactions of lithium amides with the goal of improve existing synthetic methods and developing new ones. We continue to focus on the three most important amides: lithium hexamethyldisilazide, lithium diisopropyiamide, and lithium tetramethylpiperidide. The case studies to be investigated include: (1) ketone and ester enolizations;(2) imine lithiations;(3) epoxide eliminations;(4) ortholithiations;(5) N-alkylations;(6) N-arylations;and (7) N-acylations. These case studies touch on the preponderance of the chemistry of lithium amides. Each poses unique questions and offers unique opportunities. Through an understanding of the mechanistic principleswe learn to control reactivity and selectivity. We use a uniquely integrated approach allows a combination of NMR spectroscopy, solution kinetics, and computational chemistry are brought to bear on the problems. By bringing synthetic organic, physical organic, analytical, and computational chemistry together under one roof, we reveal the consequences of soIvation and aggregation with an unprecedented clarity.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Lees, Robert G
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Cornell University
Schools of Arts and Sciences
United States
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Mack, Kyle A; Collum, David B (2018) Case for Lithium Tetramethylpiperidide-Mediated Ortholithiations: Reactivity and Mechanisms. J Am Chem Soc 140:4877-4883
Algera, Russell F; Ma, Yun; Collum, David B (2017) Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Arene Metalations. J Am Chem Soc 139:15197-15204
Reyes-Rodríguez, Gabriel J; Algera, Russell F; Collum, David B (2017) Lithium Hexamethyldisilazide-Mediated Enolization of Acylated Oxazolidinones: Solvent, Cosolvent, and Isotope Effects on Competing Monomer- and Dimer-Based Pathways. J Am Chem Soc 139:1233-1244
Algera, Russell F; Ma, Yun; Collum, David B (2017) Sodium Diisopropylamide: Aggregation, Solvation, and Stability. J Am Chem Soc 139:7921-7930
Mack, Kyle A; McClory, Andrew; Zhang, Haiming et al. (2017) Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the E/Z Selectivities. J Am Chem Soc 139:12182-12189
Li, Beryl X; Le, Diane N; Mack, Kyle A et al. (2017) Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki-Miyaura Coupling. J Am Chem Soc 139:10777-10783
Yu, Kai; Lu, Ping; Jackson, Jeffrey J et al. (2017) Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries. J Am Chem Soc 139:527-533
Algera, Russell F; Gupta, Lekha; Hoepker, Alexander C et al. (2017) Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned about Rate Limitation. J Org Chem 82:4513-4532
Algera, Russell F; Ma, Yun; Collum, David B (2017) Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Alkene Isomerizations and Diene Metalations. J Am Chem Soc 139:11544-11549
Ma, Yun; Algera, Russell F; Collum, David B (2016) Sodium Diisopropylamide in N,N-Dimethylethylamine: Reactivity, Selectivity, and Synthetic Utility. J Org Chem 81:11312-11315

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