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.
Subject(s)
Lithium/chemistry , Quinazolines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Furans , Magnetic Resonance Spectroscopy/methods , Quinazolines/chemistry , Reverse Transcriptase Inhibitors/chemistry , StereoisomerismABSTRACT
Low-temperature (6)Li, (13)C, and (15)N NMR spectroscopies reveal that mixtures of lithium cyclopropylacetylide or lithium phenylacetylide (RCCLi) and a vicinal amino alkoxide derived from camphor (R*OLi) in THF/pentane afford an asymmetric (RCCLi)(3)(R*OLi) mixed tetramer and a C(2)-symmetric (RCCLi)(2)(R*OLi)(2) mixed tetramer depending on the stoichiometries. The corresponding (RCCLi)(R*OLi)(3) mixed tetramer is not observed. R*OLi-mediated additions of PhCCLi to benzaldehyde proceed with up to an 8:1 enantiomeric ratio that depend on both the choice of R*OLi and the PhCCLi/R*OLi stoichiometries. The results are considered in light of a previously proposed mechanism for the 1,2-addition to a trifluoromethyl ketone.
Subject(s)
Camphor/chemistry , Ketones/chemistry , Lithium Compounds/chemistryABSTRACT
Low-temperature (6)Li, (13)C, and (15)N NMR spectroscopies reveal that mixtures of n-BuLi and (1R,2S)-R'(2)NCH(R)CH(Ph)OLi (ROLi; R = Ph or Me; R'(2)N = pyrrolidino or Me(2)N) in THF/pentane afford a (n-BuLi)(3)(ROLi) (3:1) mixed tetramer and a C(2)-symmetric (n-BuLi)(2)(ROLi)(2) (2:2) mixed tetramer depending on the proportions of the reactants. The corresponding (n-BuLi)(ROLi)(3) (1:3) mixed tetramer is not observed. ROLi-mediated additions of n-BuLi to benzaldehyde proceed with up to 21:1 enantiomeric ratios that depend on the n-BuLi/ROLi stoichiometries. The enantioselectivities are considered in light of a previously posited mechanism involving reaction via the C(2)-symmetric 2:2 mixed tetramer.
Subject(s)
Lithium/chemistry , Organometallic Compounds/chemistry , Alkynes , Benzaldehydes/chemistry , Benzoxazines , Cyclopropanes , Epoxy Compounds/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Oxazines/chemistry , Reverse Transcriptase Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
One- and two-dimensional (6)Li and (15)N NMR spectroscopic studies of lithium diisopropylamide (LDA) solvated by substoichiometric concentrations of oxetane, THF, Et(2)O, and diisopropylamine are described. Partially solvated dimers and trimers are identified. Possible benefits of carrying out organolithium chemistry at low ligand concentrations are discussed.
