title: NMR spectroscopic investigations of mixed aggregates underlying highly enantioselective 1,2-additions of lithium cyclopropylacetylide to quinazolinones.
abstract: The solution structures of mixed aggregates derived from lithium alkoxides and lithium acetylides were investigated as part of a program to develop practical syntheses of quinazolinone-based nonnucleoside reverse transcriptase inhibitors. Low-temperature (6)Li, (13)C, and (15)N NMR spectroscopies reveal that mixtures of lithium cyclopropylacetylide (RCCLi), a (+)-carene-derived amino alkoxide (ROLi), and lithium hexamethyldisilazide (LiHMDS) in THF/pentane afford a (RCCLi)(3)(ROLi) mixed tetramer, a C(2)-symmetric and asymmetric (RCCLi)(2)(ROLi)(2) mixed tetramer, and a C(3)-symmetric (RCCLi)(ROLi)(3) mixed tetramer. Analogous mixtures of RCCLi/ROLi in Et(2)O and Me(2)NEt also provide 3:1, 2:2, and 1:3 mixed tetramers. The stereochemistry of aggregation is highly sensitive to the medium. The C(2)-symmetric (RCCLi)(2)(ROLi)(2) mixed tetramer is formed in Et(2)O, whereas the asymmetric isomer is formed in Me(2)NEt. LiHMDS in THF is shown to be an efficient proton scavenger without forming LiHMDS-RCCLi or LiHMDS-ROLi mixed aggregates. LiHMDS-RCCLi mixtures form mixed aggregates in Me(2)NEt.
authors.affiliation: DuPont Pharmaceuticals, Chemical Process Research and Development, Chambersworks, PRF-112, Deepwater, New Jersey 08023, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Parsons
authors.forename: J M
authors.initials: JM
authors.lastname: Fortunak
authors.forename: R L
authors.initials: RL
authors.lastname: Dorow
authors.forename: G D
authors.initials: GD
authors.lastname: Harris
authors.forename: G S
authors.initials: GS
authors.lastname: Kauffman
authors.forename: W A
authors.initials: WA
authors.lastname: Nugent
authors.forename: M D
authors.initials: MD
authors.lastname: Winemiller
authors.forename: T F
authors.initials: TF
authors.lastname: Briggs
authors.forename: B
authors.initials: B
authors.lastname: Xiang
authors.forename: D B
authors.initials: DB
authors.lastname: Collum
mesh_terms: D005663:Furans; D008094:Lithium / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D005663:Furans; D011799:Quinazolines; D018894:Reverse Transcriptase Inhibitors; C018674:tetrahydrofuran; D008094:Lithium