Organolithium reagents are used in both academic and industrial laboratories to carry out complex syntheses of medicinally important compounds. The underlying solvent-dependent aggregates and mechanisms of reaction are as complex as in any subdiscipline in organometallic chemistry. We are the only group in the world with expertise in synthetic organic, organometallic, physical organic, analytical, and computational chemistry together in a single laboratory to produce fully integrated studies of structure, mechanism, and selectivity. In this proposal, we continue studies of the chemistry of lithium enolates used prominently to form C-C bonds. The program is fully integrated starting from a synthetic goal, observation, or question. Through a combination of structural and mechanistic studies we answer key questions or offer solutions to key problems. In this proposal we will focus on several classes of enolate that each present unique challenges: (1) We will survey a variety of synthetically important, highly functionalized enolates that remain uncharacterized to date. (2) Lactam and lactone enolates that are central to a collaboration with Pfizer to enhance selectivity in an asymmetric synthesis will serve as templates for evaluating basic structure-reactivity relationships. (3) Oxazolidinone-derived enolates developed by Evans and coworkers will provide basic mechanistic insights into this iconic class of reactive intermediate as well as offer qualitative probes into how structures of heteroaggregates can influence the stereochemistry of functionalizations. (4) Glycinimine-derived enolates offer an especially diverse array of aggregated forms, which will allow us to correlate aggregate structure with mechanism and stereocontrol of functionalizations. (5) ?-allyloxy ester enolates central to [2,3]-sigmatropic rearrangements present both interesting structural challenges and will be investigated to show whether the rearrangement occurs within an aggregate framework. (6) Lithiated amino alkoxides that played vital roles in Merck's and DuPont's asymmetric syntheses of reverse transcriptase inhibitors will be evaluated for their capacity to impart high aggregate control and, in turn, high stereocontrol in reactions of enolates described in the parts 1-5.
Lithium enolates and related O-lithiated species are reactive intermediates used by both academic and pharmaceutical process chemistry laboratories. Pfizer reported that 44% of all scaled up carbon-carbon bond forming reactions involved enolates. Our structural and mechanistic studies designed to understand and improve their efficacy have led to collaborations with process groups at several major pharmaceutical companies as well as several academic laboratories.
|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|
|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|
|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|
|Ma, Yun; Stivala, Craig E; Wright, Ashley M et al. (2013) Enediolate-dilithium amide mixed aggregates in the enantioselective alkylation of arylacetic acids: structural studies and a stereochemical model. J Am Chem Soc 135:16853-64|
|De Vries, Timothy S; Bruneau, Angela M; Liou, Lara R et al. (2013) Azaaldol condensation of a lithium enolate solvated by N,N,N',N'-tetramethylethylenediamine: dimer-based 1,2-addition to imines. J Am Chem Soc 135:4103-9|
|Tomasevich, Laura L; Collum, David B (2013) Structure determination using the method of continuous variation: lithium phenolates solvated by protic and dipolar aprotic ligands. J Org Chem 78:7498-507|
|De Vries, Timothy S; Goswami, Anandarup; Liou, Lara R et al. (2009) Lithium phenolates solvated by tetrahydrofuran and 1,2-dimethoxyethane: structure determination using the method of continuous variation. J Am Chem Soc 131:13142-54|
|Liou, Lara R; McNeil, Anne J; Toombes, Gilman E S et al. (2008) Structures of beta-amino ester enolates: new strategies using the method of continuous variation. J Am Chem Soc 130:17334-41|
|Gruver, Jocelyn M; Liou, Lara R; McNeil, Anne J et al. (2008) Solution structures of lithium enolates, phenolates, carboxylates, and alkoxides in the presence of N,N,N',N'-tetramethylethylenediamine: a prevalence of cyclic dimers. J Org Chem 73:7743-7|
|Liou, Lara R; McNeil, Anne J; Ramirez, Antonio et al. (2008) Lithium enolates of simple ketones: structure determination using the method of continuous variation. J Am Chem Soc 130:4859-68|