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 sub discipline 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 dialkylamides used prominently as the base of choice for difficult metalations central to many C-C bond forming processes. 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 pressing topics including: (1) We will complete studies of lithium diisopropylamide (LDA)-mediated metalations that all occur under the synthetically prominent conditions (THF at -78 oC) in which, ironically, complexity reaches a zenith because the aggregate-aggregate exchanges are not at equilibrium. (2) Related studies will focus on poorly understood LDA-LiX mixed aggregation effects observed under equilibrium conditions. (3) A collaboration starting with Amgen and expanding to include Zakarian (UCSB) will explore the structural and mechanistic basis of highly enantioselective reactions using a chiral dilithiated tetraamine. (4) Asymmetric C-N bond formation via 1,4-additions will be examined from a number of angles, all founded on previous studies in our lab. (5) The most overlooked of the three most prominent lithium amides-lithium tetramethylpiperdide-will be studied with the goal of expanding our understanding of how it metalates as well as developing pharmaceutically important hydrocarbon-soluble analogs. (6) Studies in collaboration with Paul Knochel of the rapidly developing class of tetramethylpiperidides based on magnesium and zinc will be examined. Overall, the work described in 6 aims promises to expand our most basic understanding of lithium amide structure-reactivity relationships and develop methods for use in organic synthesis.

Public Health Relevance

Lithium amides are reactive intermediates used by both academic and pharmaceutical process chemistry laboratories on a daily basis around the globe. Some are the most commonly used reagents in organic synthesis. Our structural and mechanistic studies are designed to understand and improve their efficacy and have led to advances through collaborations with major pharmaceutical companies.

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
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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
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
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
Liang, Jun; Hoepker, Alexander C; Algera, Russell F et al. (2015) Mechanism of Lithium Diisopropylamide-Mediated Ortholithiation of 1,4-Bis(trifluoromethyl)benzene under Nonequilibrium Conditions: Condition-Dependent Rate Limitation and Lithium Chloride-Catalyzed Inhibition. J Am Chem Soc 137:6292-303
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
Liang, Jun; Hoepker, Alexander C; Bruneau, Angela M et al. (2014) Lithium diisopropylamide-mediated lithiation of 1,4-difluorobenzene under nonequilibrium conditions: role of monomer-, dimer-, and tetramer-based intermediates and lessons about rate limitation. J Org Chem 79:11885-902
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
Gupta, Lekha; Hoepker, Alexander C; Ma, Yun et al. (2013) Lithium diisopropylamide-mediated ortholithiation of 2-fluoropyridines: rates, mechanisms, and the role of autocatalysis. J Org Chem 78:4214-30
Hoepker, Alexander C; Collum, David B (2011) Computational studies of lithium diisopropylamide deaggregation. J Org Chem 76:7985-93
Hoepker, Alexander C; Gupta, Lekha; Ma, Yun et al. (2011) Regioselective lithium diisopropylamide-mediated ortholithiation of 1-chloro-3-(trifluoromethyl)benzene: role of autocatalysis, lithium chloride catalysis, and reversibility. J Am Chem Soc 133:7135-51

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