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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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; Biok, Naomi A; Huck, Christopher J et al. (2016) Lithium Enolates Derived from Pyroglutaminol: Aggregation, Solvation, and Atropisomerism. J Org Chem 81:4149-57
Houghton, Michael J; Collum, David B (2016) Lithium Enolates Derived from Weinreb Amides: Insights into Five-Membered Chelate Rings. J Org Chem 81:11057-11064
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
Tallmadge, Evan H; Collum, David B (2015) Evans Enolates: Solution Structures of Lithiated Oxazolidinone-Derived Enolates. J Am Chem Soc 137:13087-95
Jin, Kyoung Joo; Collum, David B (2015) Solid-State and Solution Structures of Glycinimine-Derived Lithium Enolates. J Am Chem Soc 137:14446-55
Bruneau, Angela M; Liou, Lara; Collum, David B (2014) Solution structures of lithium amino alkoxides used in highly enantioselective 1,2-additions. J Am Chem Soc 136:2885-91
Tomasevich, Laura L; Collum, David B (2014) Method of continuous variation: characterization of alkali metal enolates using ¹H and ¹?F NMR spectroscopies. J Am Chem Soc 136:9710-8
Han, Yifeng; Ma, Yun; Keresztes, Ivan et al. (2014) Preferential geminal bis-silylation of 3,4-benzothiophane is caused by the dominance of electron withdrawal by R3Si over steric shielding effects. Org Lett 16:4678-9

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