Synthesis of naphthoquinone antibiotics by intramolecular alkyne cycloaddition to carbene-chromium complexes

M. F. Semmelhack, Joseph J. Bozell, Leonard Keller, Tadahisa Sato, E. J. Spiess, W. Wulff, A. Zask

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

The reaction of carbene-chromium complexes with alkynes provides a direct route to naphthoquinone derivatives and is the key step in a new approach to the isochromanone antibiotics exemplified by deoxyfrenolicin (1) and nanaomycin A (2). While the regioselectivity of intermolecular addition of the appropriate unsymmetrical disubstituted alkyne is unfavourable, two successful approaches have been developed. Allylacetylene reacts with methoxy-(o-methoxyphenyl)methylidene-Cr(CO)5 with high regioselectivity. Bromination, lithiation, and reaction with acetaldehyde produced the desired precursor. Alkoxypalladation led to pyran ring formation and introduction of the acetate side chain. Following earlier procedures, nanaomycin A (2) was produced. A more convergent alternative involved intramolecular cycloaddition of an alkyne with the alkylidene-chromium unit. A series of model cyclizations established the feasibility and an alkyne with an ethylene glycol side chain was prepared. The ethylene glycol unit serves as the tether to hold the alkyne in place for cyclization and allows easy removal at a later stage. Deoxyfrenolicin (1) was produced in a highly convergent and efficient process.

Original languageEnglish (US)
Pages (from-to)5803-5812
Number of pages10
JournalTetrahedron
Volume41
Issue number24
DOIs
StatePublished - 1985

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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