title: Lithium Enolates Derived from Pyroglutaminol: Mechanism and Stereoselectivity of an Azaaldol Addition.
abstract: A lithium enolate derived from an acetonide-protected pyroglutaminol undergoes a highly selective azaaldol addition with (E)-N-phenyl-1-[2-(trifluoromethyl)phenyl]methanimine. The selectivity is sensitive to tetrahydrofuran (THF) concentration, temperature, and the presence of excess lithium diisopropylamide base. Rate studies show that the observable tetrasolvated dimeric enolate undergoes reversible deaggregation, with the reaction proceeding via a disolvated-monomer-based transition structure. Limited stereochemical erosion stems from the intervention of a trisolvated-monomer-based pathway, which is suppressed at low THF concentrations and elevated temperature. Endofacial selectivity observed with excess lithium diisopropylamide (LDA) is traced to an intermediate dianion formed by subsequent lithiation of the monomeric azaaldol adduct, which is characterized as both a dilithio form and a trilithio dianion-LDA mixed aggregate.
authors: Department of Chemistry and Chemical Biology Baker Laboratory, Cornell University Ithaca, New York 14853-1301, United States.
authors: Michael J
authors: MJ
authors: Houghton
authors: Department of Chemistry and Chemical Biology Baker Laboratory, Cornell University Ithaca, New York 14853-1301, United States.
authors: Christopher J
authors: CJ
authors: Huck
authors: Worldwide Medicinal Chemistry, Pfizer Global Research and Development , 445 Eastern Point Road, Groton, Connecticut 06340, United States.
authors: Stephen W
authors: SW
authors: Wright
authors: Department of Chemistry and Chemical Biology Baker Laboratory, Cornell University Ithaca, New York 14853-1301, United States.
authors: David B
authors: DB
authors: Collum
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D000838:Anions; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000737:chemistry; D007700:Kinetics; D008094:Lithium / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011437:Propylamines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013696:Temperature; D014050:Toluene / Q000737:chemistry
chemical_list: D000447:Aldehydes; D000838:Anions; D000893:Anti-Inflammatory Agents; D005663:Furans; D011437:Propylamines; D011758:Pyrroles; D012997:Solvents; C431590:pyroglutaminol; D014050:Toluene; C018674:tetrahydrofuran; C116609:3-hydroxybutanal; D008094:Lithium; C007442:diisopropylamine