Lithium enolates constitute one of the most important classes of reactive intermediate 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 enolates. We will focus on ascertaining key structure-reactivity relationships for a number of enolates including enolates derived from simple esters and ketones, beta-amino-esters, chiral carboxamides based on oxazolidinone and ephedrate auxiliaries (Evans and Myers enolates), N-methoxycarboxamides (Weinreb amides), and alpha fluoro esters. The lithium salts of chiral vicinal amino alkoxides will also be investigated. Given the limited progress toward understanding solution structures of lithium enolates reported to date, considerable effort will focus on developing and refining new methods of structure determination. The relationships of structure and reactivity will derive from case studies to be investigated including (1) alkylation, (2) acylation, (3) azaaldol condensation, and (4) nucleophilic aromatic substitution. Through an understanding of the mechanistic principles we learn to control reactivity and selectivity via a uniquely integrated approach based on a combination of NMR spectroscopy, solution kinetics, and computational chemistry. By bringing synthetic organic, physical organic, analytical, and computational chemistry together under one roof, we reveal the consequences of solvation and aggregation with an unprecedented clarity. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Schwab, John M
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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
Jermaks, Janis; Tallmadge, Evan H; Keresztes, Ivan et al. (2018) Lithium Amino Alkoxide-Evans Enolate Mixed Aggregates: Aldol Addition with Matched and Mismatched Stereocontrol. J Am Chem Soc 140:3077-3090
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
Zhang, Zirong; Collum, David B (2017) Evans Enolates: Structures and Mechanisms Underlying the Aldol Addition of Oxazolidinone-Derived Boron Enolates. J Org Chem 82:7595-7601
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
Ma, Yun; Mack, Kyle A; Liang, Jun et al. (2016) Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies. Angew Chem Int Ed Engl 55:10093-7
Tallmadge, Evan H; Jermaks, Janis; Collum, David B (2016) Structure-Reactivity Relationships in Lithiated Evans Enolates: Influence of Aggregation and Solvation on the Stereochemistry and Mechanism of Aldol Additions. J Am Chem Soc 138:345-55
Houghton, Michael J; Huck, Christopher J; Wright, Stephen W et al. (2016) Lithium Enolates Derived from Pyroglutaminol: Mechanism and Stereoselectivity of an Azaaldol Addition. J Am Chem Soc 138:10276-83
Houghton, Michael J; Biok, Naomi A; Huck, Christopher J et al. (2016) Lithium Enolates Derived from Pyroglutaminol: Aggregation, Solvation, and Atropisomerism. J Org Chem 81:4149-57

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