Luca Salvi - Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

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      Publication Details (including relevant citation   information):

      J. Am.   Chem. Soc. 2009,   131, 12483-12493


      Enantioenriched diaryl-, aryl heteroaryl-, and   diheteroarylmethanols exhibit important biological and medicinal   properties. One-pot catalytic asymmetric syntheses of these   compounds beginning from readily available aryl bromides are   introduced. Thus, lithium-bromide exchange with commercially   available aryl bromides and n-BuLi was followed by salt   metathesis with ZnCl2 to generate ArZnCl. A second   equivalent of n-BuLi was added to form the mixed   organozinc, ArZnBu. In the presence of enantioenriched amino   alcohol-based catalysts, ArZnBu adds to aldehydes to afford   essentially racemic diarylmethanols. The low enantioselectivities   were attributed to a LiCl-promoted background reaction. To   inhibit this background reaction, the chelating diamine TEEDA   (tetraethylethylene diamine) was introduced prior to aldehyde   addition. Under these conditions, enantioenriched diarylmethanols   were obtained with >90% ee. Arylations of enals generated   allylic alcohols with 81−90% ee. This procedure was unsuccessful,   however, when applied to heteroaryl bromides, which was   attributed to decomposition of the heteroaryl lithium under the   salt metathesis conditions. To avoid this problem, the metathesis   was conducted with EtZnCl, which enabled the salt metathesis to   proceed at low temperatures. The resulting   EtZn(ArHetero) intermediates (ArHetero = 2-   and 3-thiophenyl, 2-benzothiophenyl, 3-furyl, and 5-indolyl) were   successfully added to aldehydes and heteroaryl aldehydes with   enantioselectivities between 81−99%. These are the first examples   of catalytic and highly enantioselective syntheses of   diheteroarylmethanols. In a similar fashion, ferrocenyl bromide   was used to generate FcZnEt and the ferrocenyl group added to   benzaldehyde and heteroaromatic aldehydes to form ferrocene-based   ligand precursors in 86−95% yield with 96−98% ee. It was also   found that the arylation and heteroarylation of enals could be   followed by diastereoselective epoxidations to provide epoxy   alcohols with high enantio- and diastereoselectivities in a   one-pot procedure.

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