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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM077167-09
Application #
8690215
Study Section
Special Emphasis Panel (ZRG1-SBCB-R (09))
Program Officer
Lees, Robert G
Project Start
2006-05-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
9
Fiscal Year
2014
Total Cost
$296,642
Indirect Cost
$96,642
Name
Cornell University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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