Conjugate Addition of Acylate-Nickel Complexes to Quinone Monoketals: Formal Synthesis of the Naphthoquinone Antibiotics Nanaomycin A and Deoxyfrenolicin

Martin F. Semmelhack, T. Sato, L. Keller, E. J. Spiess, W. Wulff

Research output: Contribution to journalArticle

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Abstract

A direct approach to the synthesis of isochromanone antibiotics such as nanaomycin A (2) and deoxyfrenolicin (3) is the conjugate addition of a carbonyl anion equivalent to the appropriate naphthoquinone monoketal followed by trapping with an allylic halide. This provides a naphthoquinone nucleus with two side chains which are appropriate for the palladium-promoted heterocyclization developed earlier to complete the fused pyrano ring system. As previously observed in related systems, conjugate addition of carbonyl anion equivalents to benzoquinone and naphthoquinone monoketals leads to reductive cleavage as a major pathway, especially with the benzoquinone monoketals. The most general solution to the problem is the Corey-Hegedus procedure for preparation and reaction of acylate-nickel complexes. In the first tests with quinone monoketals, efficient conjugate addition is observed with naphthoquinone monoketals, and the intermediate enolate anions can be trapped with high efficiency by using allyl iodide. Manipulation of the quinone and acyl functionality allows the formation of the α-(hydroxyalkyl)naphthoquinone system, and the palladium(II)-catalyzed ring closure gives the desired isochromanone ring system. Use of the acyl-nickel complex from methyllithium and nickel carbonyl provides nanaomycin A (2), while the combination of n-propyllithium and nickel carbonyl leads to deoxyfrenolicin (3) by the same route.

Original languageEnglish (US)
Pages (from-to)5566-5574
Number of pages9
JournalJournal of Organic Chemistry
Volume50
Issue number26
DOIs
StatePublished - Jan 1 1985

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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