Asymmetric synthesis of (−)-(S,S)-homaline |
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| Authors: | Stephen G. Davies James A. LeePaul M. Roberts Jeffrey P. StonehouseJames E. Thomson |
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| Affiliation: | a Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
b Novartis Institutes for Biomedical Research, Horsham, West Sussex, RH12 5AB, UK |
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| Abstract: | The asymmetric synthesis of (−)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to methyl cinnamate to install the correct stereochemistry. Subsequent functional group manipulation of the resultant β-amino ester and Sb(OEt)3-mediated macrolactamisation was followed by homodimerisation to give (−)-(S,S)-homaline in 18% overall yield, representing the first asymmetric, and by far the most efficient synthesis of this natural product reported to date. |
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| Keywords: | (&minus )-(S,S)-Homaline Homalium alkaloids Lithium amide Conjugate addition Asymmetric synthesis |
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