Organolithium reagents can also perform enantioselective nucleophilic addition to carbonyl and its derivatives, often in the presence of chiral ligands. This reactivity is widely applied in the industrial syntheses of pharmaceutical compounds. An example is the Merck and Dupont synthesis of Efavirenz, a potent HIV reverse transcriptase inhibitor. Lithium acetylide is added to a prochiral ketone to yield a chiral alcohol product. The structure of the active reaction intermediate was determined by NMR spectroscopy studies in the solution state and X-ray crystallography of the solid state to be a cubic 2:2 tetramer.
Collum, D.B. et al. (2001). "NMR Spectroscopic Investigations of Mixed Aggregates Underlying Highly Enantioselective 1,2-Additions of Lithium Cyclopropylacetylide to Quinazolinones". J. Am. Chem. Soc. 123: 9135–9143. doi:10.1021/ja0105616.
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 6Li, 13C, and 15N 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 C2-symmetric and asymmetric (RCCLi)2(R*OLi)2 mixed tetramer, and a C3-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.
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