NMR spectroscopic investigations of mixed aggregates underlying highly enantioselective 1,2-additions of lithium cyclopropylacetylide to quinazolinones

Parsons RL; Fortunak JM; Dorow RL; Harris GD; Kauffman GS; Nugent WA; Winemiller MD; Briggs TF; Xiang BS; Collum DB

Journal of the American Chemical Society, Vol.123, No.37, 9135-9143, 2001

Parsons RL, Fortunak JM, Dorow RL, Harris GD, Kauffman GS, Nugent WA, Winemiller MD, Briggs TF, Xiang BS, Collum DB

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 Li-6, C-13, and N-15 NMR spectroscopies reveal that mixtures of lithium cyclopropylacetylide (RCCLi), a -(+)-carene-derived amino alkoxide (R*OLi), and lithium hexamethyldisilazide (LiHMDS) in THF/pentane afford a (RCCLi)(3)(R*OLi) mixed tetramer, a C-2-symmetric and asymmetric (RCCLi)(2)(R*OLi)(2) mixed tetramer, and a C-3-symmetric (RCCLi)(R*OLi)(3) mixed tetramer. Analogous mixtures of RCCLi/R*OLi in Et2O and Me2NEt also provide 3:1, 2:2, and 1:3 mixed tetramers. The stereochemistry of aggregation is highly sensitive to the medium. The C2-symmetric (RCCLi)2(R*OLi)2 mixed tetramer is formed in Et2O, whereas the asymmetric isomer is formed in Me2NEt. LiHMDS in THF is shown to be an efficient proton scavenger without forming LiHMDS-RCCLi or LiHMDS-R*OLi mixed aggregates. LiHMDS-RCCLi mixtures form mixed aggregates in Me2NEt.