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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBCB-R (09))
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Lees, Robert G
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Cornell University
Schools of Arts and Sciences
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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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