Lithium enolates constitute one of he 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. With methods to establish solution structures that dominated the first funding period largely developed, structural studies will be more targeted in support of mechanistic studies. In the most general sense, we will examine how solvation and aggregation influence reactivity. The mechanistic investigations will focus on specific classes of reaction-case studies-that include: (1) aza-aldol condensations;(2) O-silylations;(3) alkylations;(4) acylations;(5) [2,3]- and [3,3]-sigmatropic rearrangements;and (6) nucleophilic aromatic substitutions (SNAr). A uniquely integrated approach based on a combination of NMR spectroscopy, solution kinetics, and computational chemistry will develop an understanding of the mechanistic principles and how to control reactivity and selectivity. 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.

Public Health Relevance

Project Narrative Lithium enolates are reactive intermediates used by other academic and pharmaceutical process chemistry laboratories on a daily basis around the globe. Our mechanistic studies described herein are designed to understand and improve their efficacy. The project originated from collaboration with Sanofi-Aventis to develop anti-asthmatics. The proposed funding period includes a collaboration with Amgen as part of their program to synthesize treatments for colorectal cancer.

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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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
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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